April 2010
Volume 51, Issue 4
Free
Biochemistry and Molecular Biology  |   April 2010
Involvement of TGF-β Receptor– and Integrin-Mediated Signaling Pathways in the Pathogenesis of Granular Corneal Dystrophy II
Author Affiliations & Notes
  • Seung-il Choi
    From the Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, and
  • Yeong-Min Yoo
    the Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea.
  • Bong-Yoon Kim
    From the Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, and
  • Tae-im Kim
    From the Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, and
  • Hyun-ju Cho
    From the Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, and
  • So-yoen Ahn
    From the Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, and
  • Hyung Keun Lee
    From the Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, and
  • Hyun-Soo Cho
    the Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea; and
  • Eung Kweon Kim
    From the Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, and
  • Corresponding author: Eung Kweon Kim, Severance Hospital, Yonsei University, College of Medicine, Department of Ophthalmology, 134 Shinchon-dong, Seodaemun-ku, 120-752, Seoul, Korea; eungkkim@yuhs.ac
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 1832-1847. doi:10.1167/iovs.09-4149
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      Seung-il Choi, Yeong-Min Yoo, Bong-Yoon Kim, Tae-im Kim, Hyun-ju Cho, So-yoen Ahn, Hyung Keun Lee, Hyun-Soo Cho, Eung Kweon Kim; Involvement of TGF-β Receptor– and Integrin-Mediated Signaling Pathways in the Pathogenesis of Granular Corneal Dystrophy II. Invest. Ophthalmol. Vis. Sci. 2010;51(4):1832-1847. doi: 10.1167/iovs.09-4149.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: The purpose of this study was to elucidate the pathophysiological process in primary cultured corneal fibroblasts (PCFs) from normal subjects and granular corneal dystrophy (GCD) II patients, by using cDNA microarrays.

Methods.: PCFs were isolated from the corneas of normal subjects and GCD II patients who were heterozygous and homozygous for the TGFBI R124H mutation. RNA was isolated from each sample, and gene expression profiles were analyzed with a cDNA microarray consisting of approximately 29,000 genes. Cell adhesion assays were performed to confirm the functionality of the detected gene expression profiles.

Results.: Twofold differences were detected in the expression of 555 genes between wild-type and homozygous GCD II PCFs. Of these, 319 genes were upregulated, and 236 genes were downregulated in the homozygous GCD II PCFs. The most abundant and consistent changes were observed in gene families encoding signal transduction pathways involving the TGF-β receptor– and integrin-mediated signaling, cell differentiation and proliferation, immune responses, cell adhesion, extracellular matrix (ECM) proteolytic enzymes, cell cycle, cytoskeletal organization, mitochondrial energy metabolism, collagen catabolism, response to wounding, response to oxidative stress, and the ubiquitin-mediated proteasomal degradation pathway. Cell adhesion assays demonstrated that heterozygous and homozygous GCD II PCFs strongly attached to collagen-I, collagen-IV, fibronectin, and laminin, compared with wild-type cells.

Conclusions.: Alterations in the TGF-β receptor– and integrin-mediated signaling pathway may play a key role in GCD II pathophysiology. If the novel factors identified in this study are involved in GCD II pathogenesis, they could assist in designing further studies to elucidate specific mechanisms of this disease.

Granular corneal dystrophy II (GCD II) is a disorder characterized by age-dependent progressive accumulation of protein deposits in the corneal epithelia and stroma, followed by disruption of corneal transparency. GCD II is an autosomal dominant disorder caused by a point mutation (R124H) in the transforming growth factor-β-induced gene (TGFBI) on chromosome 5, region q31. 1,2 TGFBI encodes a highly conserved 683 amino acid protein (TGFBIp) that contains a secretary signal sequence and an Arg-Gly-Asp (RGD) motif that serves as a ligand recognition site for integrins. 1 TGFBIp is a component of extracellular matrix (ECM) that mediates cell adhesion and migration by interacting with integrins. 35 More recently, it has been shown that loss of TGFBIp induces cell proliferation and spontaneous tumor development in TGFBI-knockout mice. 6  
Thirty-eight different mutations in TGFBI are involved in corneal dystrophies. Remarkably, different mutations cause unique corneal dystrophy phenotypes, such as R124H in GCD II (also called Avellino corneal dystrophy), R124C in lattice corneal dystrophy type I, R555W in granular corneal dystrophy type I, and R555Q in Thiel-Behnke corneal dystrophy. 7  
The cornea is an avascular tissue located in the anterior part of the eye and consists of five layers of tissue that serve as a barrier to infection. The principal cell types of the cornea include corneal epithelial cells in the outer region, keratocytes in the middle region, and endothelial cells in the inner region. Keratocytes, also known as corneal fibroblasts, have a dendritic morphology and produce keratan sulfate proteoglycans that are necessary for the maintenance of the corneal structure and physiology, particularly for the maintenance of corneal transparency. 8,9 These cells are also responsible for the synthesis of collagen fibrils and the ECM and for stromal repair after injury or infection. 
TGFBIp plays a significant role in the health of the cornea. For example, increased production of TGFBIp by corneal fibroblasts has been detected in areas of corneal injury, 10 and ablation of the corneal stroma by laser in situ keratomileusis (LASIK) in GCD II patients accelerates TGFBIp deposition. 11,12 Overexpression of mutant TGFBI induces apoptotic cell death in human corneal epithelial cells, 13 and age-dependent retinal degeneration has been observed in transgenic mice that express a mutant form of the human TGFBI. 14 More recently, we have reported that PCFs are most susceptible to oxidative stress. 15 However, the pathophysiological process underlying GCD II has yet to be fully elucidated. To understand the pathophysiology of GCD II, we used cDNA microarray analysis to identify differential gene expression profiles between homozygous GCD II and wild-type PCFs. We also tested the ability of these cells to adhere to various ECM proteins to confirm the functional relevance of the gene expression results. 
Materials and Methods
Isolation and Culture of Primary Corneal Fibroblasts
Wild-type (n = 3), heterozygous (n = 3), and homozygous (n = 3) primary human corneal fibroblasts were prepared by using a published method. 15 Donor confidentiality was maintained according to the Declaration of Helsinki, and the protocol was approved by Severance Hospital IRB Committee (CR04124), Yonsei University. GCD II was diagnosed by DNA sequencing analysis of TGFBI mutations. Age, sex, and diagnosis in the GCD II cases are shown in Table 1. After removal of the corneal button for penetrating keratoplasty, the remaining corneal rims were harvested for culture of the normal corneal fibroblast. The medical records of the donors from the eye bank of Yonsei University Severance Hospital did not show any genetic or systemic metabolic disease. The fibroblasts grown from the pieces of corneal rims were treated as normal ones. Genetic normality of the BIGH3 gene in normal primary corneal fibroblasts was determined by DNA sequencing analysis. Table 1 presents information regarding the corneal fibroblasts used in these studies. For cDNA microarray analysis, six samples (normal sample pairs 1, 2, and 3; and homozygous sample pairs 1, 2, and 3) were analyzed, excluding the heterozygous sample. For RT-PCR studies, the samples were prepared by pooling total RNA from two samples (Table 1, pairs 1 and 2). The sample pairs 1 and 2 were used for Western blot analysis. For the cell adhesion assay, nine samples (normal, heterozygous, and homozygous sample pairs 1, 2, and 3) were analyzed. 
Table 1.
 
Pairs of GCD II and Normal Samples
Table 1.
 
Pairs of GCD II and Normal Samples
Pair Normal Cornea Sex/Age Mean Age Heterozygous Sex/Age Mean Age Homozygous Sex/Age Mean Age Use of Samples
1 F/20 F/37 F/13 Microarray
RT-PCR
Western blot
Cell-adhesion assay
2 M/10 25.3 F/20 35.3 M/10 16.6 Microarray
RT-PCR
Cell-adhesion assay
3 M/45 F/49 F/27 Microarray
Cell-adhesion assay
RNA Extraction and Gene Expression Profiling
Transcriptional profiles were evaluated in three independent cell preparations, by using a cDNA microarray (GeneChip Human Gene 1.0 ST Array, GeneChip; Affymetrix, Santa Clara, CA) containing approximately 29,000 genes. To determine a variation and average changes (x-fold) in the expression of different genes in each sample and to compare these samples, we analyzed six samples (normal sample pairs 1, 2 and 3, and homozygous samples pair 1, 2, and 3) for new microarray analysis without total RNA pooling. Total RNA was extracted from the PCFs (TRIzol; Invitrogen, Carlsbad, CA) followed by purification (RNeasy kit; Qiagen, Valencia, CA) to remove residual DNA. The concentration of total RNA was determined by UV spectrophotometry (ND-1000 UV-Vis Spectrophotometer; Nanodrop Technologies, Wilmington, DE). Two quality controls were used for each RNA sample: (1) an A260/A280 ratio between 1.7 and 2.3; and (2) an electropherogram showing two distinct ribosomal peaks corresponding to either 18S and 28S for eukaryotic RNA bands at a ratio of 28S/18S of >0.5 with minimal or no degradation. The arrays were scanned (GeneChip Scanner 3000 7G; Affymetrix), raw signal intensities were normalized (GeneChip Operating Software [GCOS] algorithm; Affymetrix), and the data were analyzed (Gene Chip DNA Analysis Software [GDAS], ver. 2.0 according to the Affymetrix GeneChip Expression Analysis Technical Manual; http://www.affymetrix.com). We detected a twofold change in differential gene expression between the normal and homozygous samples. For statistical data analysis, we used a two-tailed unpaired Student's t-test (P < 0.05), to assess significant differences between the two cell types. 
Reverse Transcription–Polymerase Chain Reaction
Two micrograms of total RNA was reverse transcribed into cDNA (Superscript II reverse transcriptase; Invitrogen, Carlsbad, CA) and an Oligo (dT) primer (Invitrogen). The cDNA was amplified by using primers derived from the sequence of the selected differentially expressed genes, and β-actin expression was used as the control. Amplification products were visualized by electrophoresis in 1.2% agarose gels containing ethidium bromide. Specific RT-PCR primer sets and annealing temperatures are listed in Table 2
Table 2.
 
PCR Primer Pairs
Table 2.
 
PCR Primer Pairs
Genes Accession Number Forward Primers Reverse Primers Product Size (bp) Annealing Temp. (°C)
FMOD NM_002023 5′-GGAAGAGGGGATCTTTGGAC-3′ 5′-CCACCACTCATGCTTTTCCT-3′ 199 60
SOD-2 NM_001024466 5′-CGTCACCGAGGAGAAGTACC-3′ 5′-CTGATTTGGACAAGCAGCAA-3′ 196 59
TGF1 NM_000660 5′-GGGACTATCCACCTGCAAGA-3′ 5′-CCTCCTTGGCGTAGTAGTCG-3′ 239 60
TGF2 NM_001135599 5′-CCGGAGGTGATTTCCATCTA-3′ 5′-CTCCATTGCTGAGACGTCAA-3′ 287 58
TGF3 NM_003239 5′-GAGTCAGAGCCCAGCAAAAC-3′ 5′-AGAAGGAGGGAGGAAAACCA-3′ 246 58
TGFB1 NM_000358 5′-GTGTGTGCTGTGCAGAAGGT-3′ 5′-TTGAGAGTGGTAGGGCTGCT-3′ 172 58
β-Actin NM_001101 5′-GGACTTCGAGCAAGAGATGG-3′ 5′-AGCACTGTGTTGGCGTACAG-3′ 234 58
Preparation of Cell Lysates and Western Blot Analysis
Cell lysates were prepared in radio immunoprecipitation assay (RIPA) buffer (pH 7.4; containing a Complete Mini Protease Inhibitor Tablet; Roche Diagnostics, Indianapolis, IN). Crude cell lysates were centrifuged at 10,000g for 10 minutes at 4°C, to remove nuclear fragments and tissue debris. A portion of the supernatant was used to determine the total protein concentration with a bicinchoninic acid protein assay (BCA; Kit; Pierce, Rockford, IL), and equal amounts of each sample were analyzed by Western blot, as described previously. 15 The following antibodies were used: anti-integrin α2 (1:1000; Chemicon, Temecula, CA); anti-TGF-β receptors I, II, and III (1:200, 1:200, and 1:100, respectively; Santa Cruz Biotechnology, Santa Cruz, CA); and anti-fibronectin (1 μg/mL; Calbiochem, San Diego, CA). Horseradish peroxidase (HRP)-conjugated anti-mouse IgG or anti-rabbit IgG at 1:5000 were used as secondary antibodies (GE Healthcare, Piscataway, NJ). Immunoblots were developed using enhanced chemiluminescence (ECL) as described by the manufacturer (Pierce, Rockford, IL). Each immunoreactive protein band was image scanned, and optical densities were quantified (ImageJ software, version 1.37; developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at http://rsb.info.nih.gov/ij/index.html) and were corrected by background subtraction and normalized to the intensity of the corresponding β-actin protein bands. 
Cell–ECM Adhesion Profile Assays
Cell adhesion assays were performed using the ECM cell adhesion array kit (Cytomatrix; Chemicon International) according to the manufacturer's instructions. Nine samples (three samples for each of normal, heterozygous, and homozygous corneal fibroblast) were analyzed, and each experiment was repeated three times. 
Statistical Analysis
Results were evaluated for significance (P < 0.05) with one-way ANOVA followed by Newman-Keuls multiple comparison tests. Results are expressed as the mean ± SD (Prism ver. 4.0; Graph Pad Software Inc, San Diego, CA). 
Results
Gene Expression Profiles in Wild-Type and Homozygous GCD II PCFs
The GeneChip Human Gene 1.0 ST Array (Affymetrix) is a whole-transcript analysis chip composed of approximately 29,000 genes. To identify specific genes involved in the pathogenesis of GCD II, we compared the gene expression profiles between primary cultured wild-type and homozygous GCD II corneal fibroblasts. We detected twofold differences in the expression of 555 genes between these two cell types. Of these, 319 of these genes were upregulated and 236 were downregulated in the homozygous GCD II PCFs compared with wild-type (Table 3). Characterization of these genes into ontology groups suggests that GCD II-specific changes largely relate to changes in signal transduction (17%), cell cycle (13%), immune response (13%), cell adhesion (9%), cell differentiation (9%), cytoskeleton (9%), cell proliferation (6%), extracellular space (6%), cell–cell signaling (5%), response to wounding (5%), mitochondrion (2%), ubiquitin cycle (2%), endopeptidase activity (2%), TGF-β receptor signaling pathway (1%), integrin-mediated signaling pathway (1%), collagen (1%), and response to oxidative stress (1%) (Fig. 1). Specific genes that were markedly upregulated were IFI44L (43.5-fold, P < 0.0017777), IF16 (17.0-fold, P < 0.0002129), SFRP4 (16.5-fold, P < 0.0000311), PDEPDC6 (15.2-fold, P < 0.0000081), JARID1D C3 (15.2-fold, P < 0.0000078), OAS2 (12.9-fold, P < 0.0006065), XAF1 (14.1-fold, P < 0.0005192), STEA2P (10.2-fold, P < 0.0000087), and CLDN1 (10.2-fold, P < 0.0002109) (Table 4). The most downregulated genes were DDX3Y (−59.9-fold, P < 0.0002855), FBN2 (−47.8-fold, P < 0.0000903), RPS4Y1 (−27.2-fold, P < 0.0000016), EIF1AY (−19.5-fold, P < 0.0014353), RELN (–17.4-fold, P < 0.0001692), USP9Y (–16.3-fold, P < 0.0000009), KRT34 (−12.1-fold, P < 0.0000017), NLGN4Y (−11.8-fold, P < 0.0001143), UTY (−11.2-fold, P < 0.0000027), CYorf15B (−11.1-fold, P < 0.0000012), and CDH6 (−10.2-fold, P < 0.0000005) (Table 5). We next confirmed the differential expression of genes identified by the microarray using RT-PCR. We tested the expression patterns of 10 representative genes in wild-type and homozygous GCD II PCFs and found that their relative expression levels were similar to those identified by the microarray (Figs. 2A, 2B). For example, expression of FMOD and SOD2 was increased in homozygous GCD II PCFs as opposed to that in wild-type cells. Expression of TGFBI, TGFB1, TGFB2, and TGFB3 was the same in heterozygous GCD II, homozygous GCD II, and wild-type PCFs. 
Table 3.
 
GO Analysis of Genes Up- and Downregulated in GCD II CFBs
Table 3.
 
GO Analysis of Genes Up- and Downregulated in GCD II CFBs
GO ID GO Category Genes
Up Down n
GO:0007165 Signal transduction SFRP4, C3, GRP, TLR3 CXCL5, CXCL6, AHR, DTNA, CCL26, TNFAIP6, F2RL2, TAS2R43, GDF15, LPHN2, TNFRSF10A, TLR4, ANGPT1, TGFBR3, PTGER4, RASSF2, TLR1, ANK2, CLIC2, TNC, MAPK10, PBEF1, RAPH1, IRAK3 ARHGAP118, FGL2, PTGER2 ARHGAP11A, CAMK4, GPSM2, IGFBP5, CXCL12, TRHDE 37
GO:0007267 Cell-cell signaling IL8, MME, STC1, CXCL5, CXCL6, CCL2, CCL26, TNFAIP6, GDF15, EFNA5 LIF, PBEF1 INHBA, CXCL12, DLG7, TRHDE 15
GO:0007229 Integrin-mediated signaling pathway ITGB3 ITGA8 2
GO:0005615 Extracellular space SFRP4, SCG2, GRP, APOL1, IGFBP2, IL8, STC1, CXCL5, CXCL1, CXCL6, CCL2, CFH, CCL26, AKRIB1, CFHR1, MMP3, SULF2, APOD, CXCL2, LGALS3BP, CSF1, GDF15, GREM2, CLU, EFNA5, PLA2R1, WFDC1, LIF, PAPPA, TNFAIP2 BRCA2, GREM1, PSG7, CXCL12, MMP1, PSG5, RELN 37
GO:0030574 Collagen catabolism MMP3 MMP1 2
O:0001306 Response to oxidative stress SOD2, OSGIN2 2
GO:0007179 Transforming growth factor-beta receptor signaling pathway GDF15, TGFBR3 2
GO:0007155 Cell adhesion CLDN1, PCDHB3, CCL2 TNFAIP6, LGALS3BP, ROBO1, CNTNAP2, ITGB3, COL8A1, SRPX, ADAM23, RASSF2, HMCN1, TNC, LAMC2, CASK, THBS3, PCDHB13, NFASC AEBP1, PCDH18, TROAP, DSG2, HAPLN1, CDH18, CXCL12, NLGN1, EDIL3, CDH6, NLGN4Y, RELN 31
GO:0007156 Homophilic cell adhesion PCDHB3, ROBO1, PCDHB2 PCDHB4, PCDHB13 PCDH18, CDH10, DSG2, CDH18, CDH6 10
GO:0030155 Regulation of cell adhesion ICAM1, IL8, LAMA3 3
GO:0006955 Immune response IF16, OAS2, OAS1, IFI27, IFIT3, HLA-DPA1, IL8, CXCL5, CXCL1, CXCL6, DPP4, CCL26, IGJ, IFI30, CXCL2, PSMB9, ILIR1, TAP1, PTGER4, HLA-DPB1, MR1, LIF, HLA-E, HLA-C, MICA, IRF1, HLA-E, HLA-C, IFIT5, IFITM3, HLA-B, PSMB8, MICA, HLA-B, HLA-DPB1 EXO1, CXCL12, GBP3 37
GO:0006954 Inflammatory response C3, SCG2, IL8, TLR3, CXCL5 CXCL1, CXCL6, CCL2, CCL26, TNFAIP6, CXCL2, ILIR1, AOX1, TLR4, EPHX2, TLR1 CXCL12 17
GO:0006958 Complement activation, classic pathway C3, CIS, SERPING1, CF1, CLU 5
GO:0006956 Complement activation, classic pathway CFHR1, CFB 2
GO:0002474 Antigen processing and presentation of peptide antigen via MHC class I HLA-E, HLA-C, MICA, HLA-B, MICA, 5
GO:0019885 Antigen processing and presentation of endogenous ARTS-1 LRAP 2
GO:0030154 Cell differentiation SFRP4, FRZB, CSF1, TTLL7, DUSP6, EFNA5, FRK, PAPPA, DCLK1 SEMA3D, BEX1, CENPF, STMN1, ITGA8, PEG10 15
GO:0008283 Cell proliferation CREG1 KIF2C, KIF15, TPX2 8
GO:0008285 Negative regulation of cell proliferation IL8, CXCL1, RARRES3, FRK, GPNMB 5
GO:0005856 Cytoskeleton FRMD4B, PLEKHH2, FLG, EPB4IL5, MAP9, RAPH1 PKP2, DSG2, SHROOM3, ACTC1 10
GO:0005739 Mitochondrion IFI6, OAS2, OAS1, SOD2, AK3L1, ACSL5, PDK3, DMGDH, LACTB, BDH2, BNIP3, SQRDL KIAA0101 13
GO:0007049 Cell cycle PDPN, RASSF2, MAP9, MAPK13 SGOL2, FANC1, CDC2, CLSPN, CI4orf106, UBE2C, C1T, SMC4, RACGAP1, UHRF1, CKS2, CCNF, CDCA8, NCAPD2, WEE1, FBXO5, CENPE, ERCC6L, KIFC1, ESCO2, KIF23, SGOLI, KIFC1, CDCA3, PRC1, NDC80, NUSAP1, BUBIB, PLK1, CDCA2, NCAPG, FAM64A, SPC25, CCNB2, CEP55, CDC20, ASPM, ANLN, FOXM1, SPAG5, NUF2, DLG7 46
GO:0051318 G1 phase PRUNE2, PRUNE2 2
GO:0007601 Visual perception GLRB, HMCN1 GJA7 3
GO:0004252 Serine-type endopeptidase activity CFB, CORIN, PRSS23, CF1 RELN 5
GO:0004867 Serine-type endopeptidase inhibitor activity SERPING1, SERPIN11, WFDC1 SERPINB7 4
GO:0004190 Aspartic-type endopeptidase activity PEG10 1
GO:0004222 Metalloendopeptidase activity ADAM23 1
GO:0030574 Collagen catabolic process MMP3 MMP1 2
GO:0030199 Collagen fibrit organization COLI4A1 1
GO:0005581 Collagen COL14A1 1
GO:0004232 Interstitial collagenase activity MMP1 1
GO:0007181 Transforming growth factor beta receptor complex assembly FMOD 1
GO:0007179 Transforming growth factor-beta receptor signaling pathway GDF15, TGFBR3 2
GO:0030512 Negative regulation of transforming growth factor beta receptor signaling pathway PEG10 1
GO:0006512 Ubiquitin cycle FBXO32, FBXO16, FBXL2 UBE2C, UHRF1, FBXO5, CDCA3, CDC20, USP9Y 9
GO:0004842 Ubiquitin-protein ligase activity FBXL2 UBE2C 2
GO:0009611 Response to wounding F2RL2, GAP43 2
GO:0006979 Response to oxidative stress SOD2, PRNP 2
GO:0004364 Glutathione S-transferase activity GSTM1 1
Figure 1.
 
Gene ontological classification of differentially regulated genes in homozygous GCD II PCFs. Genes that were differentially expressed at a minimum of twofold were included in the analysis. Numbers in parentheses represent the number of genes.
Figure 1.
 
Gene ontological classification of differentially regulated genes in homozygous GCD II PCFs. Genes that were differentially expressed at a minimum of twofold were included in the analysis. Numbers in parentheses represent the number of genes.
Table 4.
 
Upregulated Homozygous GCD II–Related Genes
Table 4.
 
Upregulated Homozygous GCD II–Related Genes
No. Gene Accession Gene Symbol Gene Description Change P
1 NM_006820 IFI44L Interferon-induced protein 44-like 43.5 0.0017777
2 NM_022872 IFI6 Interferon, alpha-inducible protein 6 17.1 0.0002129
3 NM_003014 SFRP4 Secreted frizzled-related protein 4 16.5 0.0000311
4 NM_022783 DEPDC6 DEP domain containing 6 15.2 0.0000081
5 NM_000064 C3 Complement component 3 15.2 0.0000078
6 NM_002535 OAS2 2′-5′-Oligoadenylate synthetase 2, 69/71kDa 12.9 0.0006065
7 NM_017523 XAF1 XIAP associated factor-1 11.4 0.0005192
8 NM_152999 STEAP2 Six transmembrane epithelial antigen of the prostate 2 10.2 0.0000087
9 NM_021101 CLDN1 Claudin I 10.2 0.0002109
10 NM_016816 OAS1 2′,5′-Oligoadenylate synthetase 1, 40/46kDa 9.7 0.0035803
11 ENST00000260184 FLJ20035 Hypothetical protein FLJ20035 (FLJ20035), mRNA 9.7 0.0013714
12 NM_005532 IFI27 Interferon, alpha-inducible protein 27 9.1 0.0003262
13 NM_003469 SCG2 Secretogranin II (chromogranin C) 8.4 0.0000092
14 NM_002091 GRP Gastrin-releasing peptide 8.3 0.0000031
15 NM_001031683 IFIT3 Interferon-induced protein with tetratricopeptide repeats 3 7.6 0.0061816
16 uc002feh.1 CHST6 Carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6 7.6 0.0000052
17 NM_139072 DNER Delta/notch-like EGF repeat containing 7.5 0.0000055
18 NM_080284 ABCA6 ATP-binding cassette, sub-family A (ABC1), member 6 7.3 0.0000006
19 NM_203349 SHC4 SHC (Src homology 2 domain containing) family, member 4 7 0.0000941
20 NM_020299 AKRIBI0 Aldo-keto reductase family 1, member B10 (aldose reductase) 6.9 0.0000183
21 NM_007168 ABCA8 ATP-binding cassette, sub-family A (ABC1), member 8 6.7 0.0001116
22 NM_006417 IFI44 Interferon-induced protein 44 6.7 0.002165
23 NM_033554 HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 6.6 0.0000318
24 NM_024574 C4orf31 Chromosome 4 open reading frame 31 6.6 0.0000578
25 NM_145343 APOL1 Apolipoprotein L, 1 6.6 0.0001028
26 NM_033554 HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 6.5 0.0002743
27 NM_033554 HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 6.5 0.0002743
28 NR_003198 SNORD114-6 Small nucleolar RNA, C/D box 114-6 6.5 0.0000037
29 NM_000597 IGFBP2 Insulin-like growth factor binding protein 2, 36kDa 6.2 0.0005975
30 NM_004163 RAB27B RAB27B, member RAS oncogene family 6.1 0.0001163
32 NM_000201 ICAM1 Intercellular adhesion molecule I (CD54), human rhinovirus receptor 6 0.0000264
33 NM_000584 IL8 Interleukin 8 5.9 0.0001314
34 NM_021110 COL14A1 Collagen, type XIV, alpha I (undulin) 5.5 0.0000128
35 NM_001024465 SOD2 Superoxide dismutase 2, mitochondrial 5.5 0.0004007
38 NM_003265 TLR3 Toll-like receptor 3 5.3 0.0012359
39 NM_152703 SAMD9L Sterile alpha motif domain containing 9-like 5.1 0.0005941
40 NM_007288 MME Membrane metallo-endopeptidase 4.8 0.0000029
41 NM_005907 MAN1A1 Mannosidase, alpha, class IA, member 1 4.7 0.0000526
42 NM_003155 STC1 Stanniocalcin 1 4.7 0.0003264
43 NM_022154 SLC39A8 Solute carrier family 39 (zinc transporter), member 8 4.7 0.0034818
44 NM_139248 LIPH Lipase, member H 4.6 0.0000636
45 NM_001002264 EPSTI1 Epithelial stromal interaction I (breast) 4.6 0.0019874
46 BC022571 PRUNE2 Prune homolog 2 (Drosophila) 4.5 0.0006296
47 NM_002994 CXCL5 Chemokine (C-X-C motif) ligand 5 4.5 0.001963
48 NM_001511 CXCL1 Chemokine (C-X-C motif) ligand I (melanoma growth stimulating activity, alpha) 4.5 0.006012
49 NM_002538 OCLN Occludin 4.4 0.00084
50 NM_018937 PCDHB3 Protocadherin beta 3 4.4 0.0000115
51 NM_145172 WDR63 WD repeat domain 63 4.3 0.0000206
52 NM_004585 RARRES3 Retinoic acid receptor responder (tazarotene induced) 3 4.3 0.0002066
53 NM_003739 AKR1C3 Aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II) 4.3 0.0000081
54 NM_002993 CXCL6 Chemokine (C-X-C motif) ligand 6 (granulocyte chemotactic protein 2) 4.3 0.0004347
55 NM_016352 CPA4 Carboxypeptidase A4 4.3 0.0000333
56 NM_017554 PARP14 Poly (ADP-ribose) polymerase family, member 14 4.2 0.0019238
57 NM_002982 CCL2 Chemokine (C-C motif) ligand 2 4.2 0.0000148
58 NM_205845 AKR1C2 Aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III) 4.2 0.0000279
59 NM_032812 PLXDC2 Plexin domain containing 2 4.1 0.0000003
60 NM_138818 PRUNE2 Prune homolog 2 (Drosophila) 4 0.0000703
61 NM_001935 DPP4 Dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2) 4 0.0000083
62 NM_001013442 EPGN Epithelial mitogen homolog (mouse) 3.9 0.0000298
63 NM_000186 CFH Complement factor H 3.9 0.0000126
64 NM_014314 DDX58 DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 3.8 0.0033267
65 NM_182767 SLC6A15 Solute carrier family 6, member 15 3.8 0.000131
66 NM_080671 KCNE4 Potassium voltage-gated channel, Isk-related family, member 4 3.7 0.0004738
67 NM_001390 DTNA Dystrobrevin, alpha 3.7 0.0000589
68 NM_175861 TMTC1 Transmembrane and tetratricopeptide repeat containing 1 3.7 0.0000083
69 NM_006072 CCL26 Chemokine (C-C motif) ligand 26 3.6 0.0000234
70 NM_144646 IGJ Immunoglobulin J polypeptide, linker protein for immunoglobulin alpha and mu polypeptides 3.6 0.0011411
71 NM_003851 CREG1 Cellular repressor of E1A-stimulated genes 1 3.6 0.0000007
72 NM_153703 PODN Podocan 3.6 0.0000006
73 NM_007115 TNFAIP6 Tumor necrosis factor, alpha-induced protein 6 3.6 0.0009063
74 NM_001628 AKR1B1 Aldo-keto reductase family 1, member B1 (aldose reductase) 3.5 0.000003
75 NM_016848 SHC3 SHC (Src homology 2 domain containing) transforming protein 3 3.5 0.000021
76 NM_018349 MCTP2 Multiple C2 domains, transmembrane 2 3.5 0.000013
77 NM_015123 FRMD4B FERM domain containing 4B 3.5 0.0000545
78 NM_015529 MOXD1 Monooxygenase, DBH-like 1 3.5 0.0000004
79 NM_198129 LAMA3 Laminin, alpha 3 3.5 0.0000003
80 NM_080283 ABCA9 ATP-binding cassette, sub-family A (ABC1), member 9 3.4 0.0002608
81 NM_000313 PROS1 Protein S (alpha) 3.4 0.0000002
82 NM_015028 TNIK TRAF2 and NCK interacting kinase 3.4 0.0016728
83 NM_004101 F2RL2 Coagulation factor II (thrombin) receptor-like 2 3.4 0.0000043
84 NM_017439 Icag7.1314 Hypothetical protein LOC54103 3.3 0.0007954
85 NM_005824 LRRC17 Leucine rich repeat containing 17 3.3 0.0000081
86 NM_001001924 MTUS1 Mitochondrial tumor suppressor 1 3.3 0.0002024
87 NM_006393 NEBL Nebulette 3.3 0.0000077
88 NM_176884 TAS2R43 Taste receptor, type 2, member 43 3.3 0.0015163
89 NM_000115 EDNRB Endothelin receptor type B 3.3 0.0010275
90 NM_153366 SVEP1 Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 3.2 0.0000004
91 NM_016246 HSD17B14 Hydroxysteroid (17-beta) dehydrogenase 14 3.2 0.0000521
92 NM_002023 FMOD Fibromodulin 3.2 0.0000113
93 NM_002113 CFHR1 Complement factor H-related 1 3.2 0.0004559
94 NM_024636 STEAP4 STEAP family member 4 3.2 0.0013693
95 NM_002422 MMP3 Matrix metallopeptidase 3 (stromelysin 1, progelatinase) 3.1 0.0000206
96 NM_018837 SULF2 Sulfatase 2 3.1 0.0000052
97 NM_017614 BHMT2 Betaine-homocysteine methyltransferase 2 3.1 0.0000017
98 NM_006332 IFI30 Interferon, gamma-inducible protein 30 3.1 0.0000761
99 NM_001463 FRZB Frizzled-related protein 3.1 0.0012231
100 NM_201442 C1S Complement component 1, s subcomponent 3.1 0.0000036
101 NM_058229 FBXO32 F-box protein 32 3.1 0.0000464
102 NM_001710 CFB Complement factor B 3.1 0.0011518
103 NM_173567 ABHD7 Abhydrolase domain containing 7 3.1 0.0016296
104 NM_001647 APOD Apolipoprotein D 3.0 0.0048695
105 NR_003578 ZNF702 Zinc finger protein 702 3.0 0.0003033
106 NM_006474 PDPN Podoplanin 3.0 0.0000074
107 NM_002089 CXCL2 Chemokine (C-X-C motif) ligand 2 3.0 0.0071753
108 NM_198520 C12orf63 Chromosome 12 open reading frame 63 3.0 0.0016097
109 NM_001012967 FLJ31033 Hypothetical protein FLJ31033 3.0 0.0010071
110 NM_018355 ZNF415 Zinc finger protein 415 3.0 0.0001087
111 NM_005103 FEZ1 Fasciculation and elongation protein zeta 1 (zygin 1) 2.9 0.0013669
112 NM_001030060 SAMD5 Sterile alpha motif domain containing 5 2.9 0.0003825
113 NM_000062 SERPING1 Serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, (angioedema, hereditary) 2.9 0.0017786
114 ENST00000326754 FLJ25801 Hypothetical protein FLJ25801 (FLJ25801), mRNA 2.9 0.00033
115 NM_001038628 B3GALNT1 Beta-1,3-N-acetylgalactosaminyltransferase 1 (globoside blood group) 2.9 0.000004
116 NM_005567 LGALS3BP Lectin, galactoside-binding, soluble, 3 binding protein 2.9 0.0004468
117 NM_000689 ALDH1A1 Aldehyde dehydrogenase 1 family, member A1 2.9 0.0019248
118 NM_000757 CSF1 Colony stimulating factor 1 (macrophage) 2.9 0.0000119
119 NM_004864 GDF15 Growth differentiation factor 15 2.9 0.0001212
120 NM_001710 CFB Complement factor B 2.9 0.0013733
121 NM_001013732 C6orf138 Chromosome 6 open reading frame 138 2.9 0.0005379
122 NM_012302 LPHN2 Latrophilin 2 2.8 0.0001229
123 NM_183376 ARRDC4 Arrestin domain containing 4 2.8 0.0000015
124 NM_007257 PNMA2 Paraneoplastic antigen MA2 2.8 0.0052895
125 ENST00000296529 TMEM144 Transmembrane protein 144 (TMEM144), mRNA 2.8 0.0056544
126 NM_052831 C6orf192 Chromosome 6 open reading frame 192 2.8 0.0000583
127 NM_004675 DIRAS3 DIRAS family, GTP-binding RAS-like 3 2.8 0.0000624
128 NM_172069 PLEKHH2 Pleckstrin homology domain containing, family H (with MyTH4 domain) member 2 2.8 0.0001397
129 NM_182969 XRRA1 X-ray radiation resistance associated 1 2.8 0.0000341
130 NM_018242 SLC47A1 Solute carrier family 47, member 1 2.8 0.0001539
131 NM_017549 EPDR1 Ependymin related protein 1 (zebrafish) 2.8 0.0000008
132 NM_203464 AK3L1 Adenylate kinase 3-like 1 2.8 0.0001709
133 NM_004827 ABCG2 ATP-binding cassette, sub-family G (WHITE), member 2 2.7 0.0000899
134 NM_003844 TNFRSF10A Tumor necrosis factor receptor superfamily, member 10a 2.7 0.0004671
135 NM_002222 ITPR1 Inositol 1,4,5-triphosphate receptor, type 1 2.7 0.0000039
136 NM_003543 HISTIH4H Histone cluster 1, H4h 2.7 0.0001016
137 NM_148954 PSMB9 Proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2) 2.7 0.003365
138 NM_148954 PSMB9 Proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2) 2.7 0.003365
139 NM_002800 PSMB9 Proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2) 2.7 0.003365
140 NM_021244 RRAGD Ras-related GTP binding D 2.7 0.0004553
141 NM_178826 TMEM16D Transmembrane protein 16D 2.6 0.0000977
142 NM_000877 IL1R1 Interleukin 1 receptor, type 1 2.6 0.0000427
143 NM_133631 ROBO1 Roundabout, axon guidance receptor, homolog 1 (Drosophila) 2.6 0.000011
144 NM_014141 CNTNAP2 Contactin associated protein-like 2 2.6 0.0000317
145 NM_001334 CTSO Cathepsin O 2.6 0.0000504
146 NM_001085423 C17orf60 Chromosome 17 open reading frame 60 2.6 0.0002676
147 NM_002045 GAP43 Growth associated protein 43 2.6 0.0000103
148 NM_024686 TTLL7 Tubulin tyrosine ligase-like family, member 7 2.6 0.0000499
149 NM_005502 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1 2.6 0.0000177
150 NM_000593 TAP1 Transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) 2.6 0.0031895
151 NM_000593 TAP1 Transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) 2.6 0.0031895
152 NM_000593 TAP1 Transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) 2.6 0.0031895
153 NM_005779 LHFPL2 Lipoma HMG1C fusion partner-like 2 2.6 0.0001421
154 NM_007047 BTN3A2 Butyrophilin, subfamily 3, member A2 2.6 0.0000841
155 NM_012472 LRRC6 Leucine rich repeat containing 6 2.5 0.0006272
156 NM_001159 AOX1 Aldehyde oxidase 1 2.5 0.000033
157 NM_017734 PALMD Palmdelphin 2.5 0.0003744
158 NM_004170 SLC1A1 Solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 2.5 0.000006
159 NM_000311 PRNP Prion protein (p27-30) (Creutzfeldt-Jakob disease, Gerstmann-Strausler-Scheinker syndrome, fatal familial insomnia) 2.5 0
160 NM_005025 SERPINI1 Serpin peptidase inhibitor, clade 1.(neuroserpin), member 1 2.5 0.0001759
161 NM_001946 DUSP6 Dual specificity phosphatase 6 2.5 0.0000949
162 NM_000212 ITGB3 Integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) 2.5 0.0001519
164 NR_003530 MEG3 Maternally expressed 3 2.5 0.0001135
165 NM_015274 MAN2B2 Mannosidase, alpha, class 2B, member 2 2.5 0.0000109
166 NM_006207 PDGFRL Platelet-derived growth factor receptor-like 2.5 0.0001507
167 NM_000722 CACNA2D1 Calcium channel, voltage-dependent, alpha 2/delta subunit 1 2.5 0.0000006
168 NM_001975 ENO2 Enolase 2 (gamma, neuronal) 2.5 0.000141
169 NM_002637 PHKA1 Phosphorylase kinase, alpha 1 (muscle) 2.5 0.0000154
170 NM_022469 GREM2 Gremlin 2, cysteine knot superfamily, homolog (Xenopus laevis) 2.5 0.0000111
171 NM_001040458 ARTS-1 Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator 2.5 0.0000227
172 NM_001962 EFNA5 Ephrin-A5 2.5 0.0000425
173 NM_001850 COL8A1 Collagen, type VIII, alpha 1 2.5 0.0000884
174 NM_014367 C3orf28 Chromosome 3 open reading frame 28 2.5 0.0038544
175 NM_024621 VEPH1 Ventricular zone expressed PH domain homolog 1 (zebrafish) 2.5 0.000141
176 NM_017901 TPCN1 Two pore segment channel 1 2.5 0.0000426
177 NM_003551 NME5 Non-metastatic cells 5, protein expressed in (nucleoside-diphosphate kinase) 2.5 0.0014518
178 NM_203380 ACSL5 Acyl-CoA synthetase long-chain family member 5 2.5 0.004572
179 NM_007036 ESM1 Endothelial cell-specific molecule 1 2.5 0.0005156
180 NM_006587 CORIN Corin, serine peptidase 2.5 0.000425
181 NM_138554 TLR4 Toll-like receptor 4 2.5 0.0000129
182 NM_000187 HGD Homogentisate 1,2-dioxygenase (homogentisate oxidase) 2.4 0.000498
183 NM_000187 HGD Homogentisate 1,2-dioxygenase (homogentisate oxidase) 2.4 0.000498
184 NM_005391 PDK3 Pyruvate dehydrogenase kinase, isozyme 3 2.4 0.0017101
185 NM_173508 SLC35F3 Solute carrier family 35, member F3 2.4 0.0002497
186 NM_000147 FUCA1 Fucosidase, alpha-L-1, tissue 2.4 0.0001624
187 NM_181785 SLC46A3 Solute carrier family 46, member 3 2.4 0.0000173
188 NM_002031 FRK Fyn-related kinase 2.4 0.0002699
189 NM_206996 SPAG17 Sperm associated antigen 17 2.4 0.0002856
190 NM_006307 SRPX Sushi-repeat-containing protein, X-linked 2.4 0.0003416
191 NM_007366 PLA2R1 Phospholipase A2 receptor 1, 180kDa 2.4 0.000002
192 NM_020041 SLC2A9 Solute carrier family 2 (facilitated glucose transporter), member 9 2.4 0.0001373
193 NM_031419 NFKBIZ Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 2.4 0.0001795
194 NM_000214 JAG1 Jagged I (Alagille syndrome) 2.4 0.0004701
195 NM_001979 EPHX2 Epoxide hydrolase 2, cytoplasmic 2.4 0.0002466
196 NM_006095 ATP8A1 ATPase, aminophospholipid transporter (APLT), Class 1, type 8A, member 1 2.4 0.0000686
197 NM_053276 VIT Vitrin 2.4 0.0000835
198 NM_001146 ANGPT1 Angiopoietin 1 2.4 0.0003832
199 NM_001040457 RHBDD2 Rhomboid domain containing 2 2.4 0.0000221
200 NM_138287 DTX3L Deltex 3-like (Drosophila) 2.4 0.0052558
201 NM_003812 ADAM23 ADAM metallopeptidase domain 23 2.4 0.0000041
202 NM_006994 BTN3A3 Butyrophilin, subfamily 3, member A3 2.4 0.0003593
204 NM_018936 PCDHB2 Protocadherin beta 2 2.4 0.0002569
205 NM_015194 MYOID Myosin ID 2.4 0.0000391
206 NM_001086 AADAC Arylacetamide deacetylase (esterase) 2.3 0.0000226
207 NM_014467 SRPX2 Sushi-repeat-containing protein, X-linked 2 2.3 0.0000049
208 NM_024726 IQCA IQ motif containing with AAA domain 2.3 0.0001621
209 NM_002016 FLG Filaggrin 2.3 0.002256
210 NM_003243 TGFBR3 Transforming growth factor, beta receptor III 2.3 0.0000001
211 NM_052867 NALCN Sodium leak channel, non-selective 2.3 0.0001055
212 NM_004337 OSGIN2 Oxidative stress induced growth inhibitor family member 2 2.3 0.0000301
213 NM_000958 PTGER4 Prostaglandin E receptor 4 (subtype EP4) 2.3 0.0006466
214 NM_001033045 GPR155 G protein-coupled receptor 155 2.3 0.0000117
215 NM_032587 CARD6 Caspase recruitment domain family, member 6 2.3 0.0007864
216 NM_021197 WFDC1 WAP four-disulfide core domain 1 2.3 0.0001014
217 NM_018938 PCDHB4 Protocadherin beta 4 2.3 0.0002702
218 NM_013391 DMGDH Dimethylglycine dehydrogenase 2.3 0.0007769
219 NM_014505 KCNMB4 Potassium large conductance calcium-activated channel, subfamily M, beta member 4 2.3 0.0000254
220 NM_172366 FBXO16 F-box protein 16 2.3 0.0000801
221 NM_203403 C9orf150 Chromosome 9 open reading frame 150 2.3 0.0009304
222 NM_007048 BTN3A1 Butyrophilin, subfamily 3, member A1 2.3 0.0002037
223 NM_014737 RASSF2 Ras association (RalGDS/AF-6) domain family 2 2.3 0.0002623
224 NM_001148 ANK2 Ankyrin 2, neuronal 2.3 0.0003172
225 NM_018421 TBC1D2 TBC1 domain family, member 2 2.3 0.002261
226 NM_000824 GLRB Glycine receptor, beta 2.3 0.000148
227 NM_002121 HLA-DPB1 Major histocompatibility complex, class II, DP beta 1 2.3 0.0011187
228 NM_001289 CLIC2 Chloride intracellular channel 2 2.3 0.0000485
229 NM_020848 KIAA1462 KIAA1462 2.3 0.0000095
230 NM_004065 CDR1 Cerebellar degeneration-related protein 1, 34kDa 2.2 0.000323
231 NM_031935 HMCN1 Hemicentin 1 2.2 0.0001081
232 NM_001621 AHR Aryl hydrocarbon receptor 2.2 0.0000101
233 NM_002231 CD82 CD82 molecule 2.2 0.0000261
234 NM_018295 TMEM140 Transmembrane protein 140 2.2 0.0008474
235 NM_002970 SAT1 Spermidine/spermine N1 acetyltransferase 1 2.2 0.0000077
236 NM_001531 MR1 Major histocompatibility complex, class I-related 2.2 0.0000163
237 NM_003043 SLC6A6 Solute carrier family 6 (neurotransmitter transporter, taurine), member 6 2.2 0.0001361
238 NM_012157 FBXL2 F-box and leucine-rich repeat protein 2 2.2 0.0000359
239 NM_002309 LIF Leukemia inhibitory factor (cholinergic differentiation factor) 2.2 0.0007509
240 NM_024763 WDR78 WD repeat domain 78 2.2 0.0017849
241 NM_021945 C6orf85 Chromosome 6 open reading frame 85 2.2 0.0017489
242 NM_001218 CA12 Carbonic anhydrase XII 2.2 0.000822
243 NM_002160 TNC Tenascin C (hexabrachion) 2.2 0.0000479
244 NM_005516 HLA-E Major histocompatibility complex, class 1, E 2.2 0.0000489
245 NM_005516 HLA-E Major histocompatibility complex, class 1, E 2.2 0.0000489
246 NM_003263 TLR1 Toll-like receptor 1 2.2 0.0014844
247 NM_002117 HLA-C Major histocompatibility complex, class 1, C 2.2 0.0000444
248 NM_000247 MICA MHC class I polypeptide-related sequence A 2.2 0.0001143
249 NM_000202 IDS Iduronate 2-sulfatase (Hunter syndrome) 2.2 0.0000043
250 NM_032857 LACTB Lactamase, beta 2.2 0.0001232
251 NM_002198 IRF1 Interferon regulatory factor 1 2.2 0.0018853
252 NM_145235 FANK1 Fibronectin type III and ankyrin repeat domains 1 2.2 0.0002057
254 NM_182943 PLOD2 Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 2.2 0.0000188
255 NM_005562 LAMC2 Laminin, gamma 2 2.2 0.0012097
256 NM_144629 RFTN2 Raftlin family member 2 2.2 0.0015459
257 NM_002581 PAPPA Pregnancy-associated plasma protein A, pappalysin 1 2.2 0.000067
258 NM_004090 DUSP3 Dual specificity phosphatase 3 (vaccinia virus phosphatase VHI-related) 2.2 0.0000206
259 NM_006291 TNFAIP2 Tumor necrosis factor, alpha-induced protein 2 2.2 0.0008835
260 NM_145176 SLC2AI2 Solute carrier family 2 (facilitated glucose transporter), member 12 2.2 0.0003708
261 NM_005516 HLA-E Major histocompatibility complex, class 1, E 2.2 0.0000376
262 NM_020909 EPB41L5 Erythrocyte membrane protein band 4.1 like 5 2.2 0.0000017
263 NM_002117 HLA-C Major histocompatibility complex; class 1, C 2.2 0.0000294
264 NM_003688 CASK Calcium/calmodulin-dependent serine protein kinase (MAGUK family) 2.2 0.0000365
265 NM_001005340 GPNMB Glycoprotein (transmembrane) nmb 2.2 0.0000069
266 NM_012420 IFIT5 Interferon-induced protein with tetratricopeptide repeats 5 2.2 0.0013319
267 NM_138980 MAPK10 Mitogen-activated protein kinase 10 2.2 0.0001154
268 NM_002350 LYN V-yes-1 Yamaguchi sarcoma viral related oncogene homolog 2.2 0.0001236
269 NM_007173 PRSS23 Protease, serine, 23 2.1 0.0000224
270 ENST00000222553 PBEF1 Pre-B-cell colony enhancing factor 1 (PBEF1), mRNA 2.1 0.0006919
271 NM_014936 ENPP4 Ectonucleotide pyrophosphatase/phosphodiesterase 4 (putative function) 2.1 0.0000373
272 NM_021626 SCPEP1 Serine carboxypeptidase 1 2.1 0.0000678
273 NM_173505 ANKRD29 Ankyrin repeat domain 29 2.1 0.0000555
274 NM_000120 EPHX1 Epoxide hydrolase 1, microsomal (xenobiotic) 2.1 0.0000223
275 NM_001039580 MAP9 Microtubule-associated protein 9 2.1 0.0003664
276 NM_005746 PBEF1 Pre-B-cell colony enhancing factor 1 2.1 0.0007562
277 NM_000204 CF1 Complement factor 1 2.1 0.0015781
278 NM_021034 IFITM3 Interferon induced transmembrane protein 3 (I-8U) 2.1 0.0000542
279 NM_004734 DCLK1 Doublecortin-like kinase 1 2.1 0.0005205
280 NM_004696 SLC16A4 Solute carrier family 16, member 4 (monocarboxylic acid transporter 5) 2.1 0.0002086
281 NM_213589 RAPH1 Ras association (RalGDS/AF-6) and pleckstrin homology domains 1 2.1 0.0000129
282 NM_002395 ME1 Malic enzyme 1, NADP(+)-dependent, cytosolic 2.1 0.0000103
283 NM_014157 CCDC113 Coiled-coil domain containing 113 2.1 0.0002231
284 NR_002157 OR2A9P Olfactory receptor, family 2, subfamily A, member 9 pseudogene 2.1 0.0008517
285 NM_007112 THBS3 Thrombospondin 3 2.1 0.0000632
286 NM_005514 HLA-B Major histocompatibility complex, class 1, B 2.1 0.000079
287 NM_018933 PCDHB13 Protocadherin beta 13 2.1 0.0006096
288 NM_138452 DHRS1 Dehydrogenase/reductase (SDR family) member 1 2.1 0.0014038
289 NM_144599 NIPA1 Non imprinted in Prader-Willi/Angelman syndrome 1 2.1 0.0000307
290 XR_019525 LOC390345 Hypothetical LOC390345 2.1 0.0045174
291 NM_024642 GALNT12 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 12 (GalNAc-T12) 2.1 0.0001604
292 NM_020422 TMEM159 Transmembrane protein 159 2.1 0.0006667
293 NM_080593 HIST1H2BK Histone cluster 1, H2bk 2.1 0.0001187
294 NM_198503 KCNT2 Potassium channel, subfamily T, member 2 2.1 0.0035322
295 NM_007199 IRAK3 Interleukin-1 receptor-associated kinase 3 2.1 0.0030475
297 NM_005514 HLA-B Major histocompatibility complex, class 1, B 2 0.0002145
298 NM_003328 TXK TXK tyrosine kinase 2 0.0010901
290 NM_005419 STAT2 Signal transducer and activator of transcription 2, 113kDa 2 0.0012848
300 NM_001039706 FLJ21062 Hypothetical protein FLJ21062 2 0.001607
301 NM_015090 NFASC Neurofascin homolog (chicken) 2 0.0000349
302 NM_004159 PSMB8 Proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7) 2 0.0001761
303 NM_004159 PSMB8 Proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7) 2 0.0001761
304 NM_004159 PSMB8 Proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7) 2 0.0001761
305 NM_000247 MICA MHC class I polypeptide-related sequence A 2 0.0000572
306 NM_002754 MAPK13 Mitogen-activated protein kinase 13 2 0.0009883
307 NM_005929 MF12 Antigen p97 (melanoma associated) identified by monoclonal antibodies 133.2 and 96.5 2 0.0001076
308 NM_005514 HLA-B Major histocompatibility complex, class 1, B 2 0.000205
309 NM_018050 MANSC1 MANSC domain containing 1 2 0.0000755
310 NM_002121 HLA-DPB1 Major histocompatibility complex, class II, DP beta 1 2 0.000209
311 NM_018317 TBC1D19 TBC1 domain family, member 19 2 0.0000012
312 NR_003322 SNORD116-7 Small nucleolar RNA, C/D box 116-7 2 0.0051387
313 NR_003320 SNORD116-5 Small nucleolar RNA, C/D box 116-5 2 0.0051387
314 NM_020139 BDH2 3-hydroxybutyrate dehydrogenase, type 2 2 0.0000086
315 NM_004052 BNIP3 BCL2/adenovirus E1B 19kDa interacting protein 3 2 0.0001215
316 NM_021199 SQRDL Sulfide quinone reductase-like (yeast) 2 0.0008101
317 NM_153704 TMEM67 Transmembrane protein 67 2 0.0019696
318 NM_001831 CLU Clusterin 2 0.0001778
319 NM_014585 SLC40A1 Solute carrier family 40 (iron-regulated transporter), member 1 2 0.0002529
Table 5.
 
Downregulated Homozygous GCD II–Related Genes
Table 5.
 
Downregulated Homozygous GCD II–Related Genes
No. Gene Accession Gene Symbol Gene Description Change P
1 NM_181503 EXOSC8 Exosome component 8 −2.0 0.0011677
2 NM_152524 SGOL2 Shugoshin-like 2 (S. pombe) −2.0 0.0050817
3 NR_002564 SNORD26 Small nucleolar RNA, C/D box 26 −2.0 0.0002281
4 NM_003534 HIST1H3G Histone cluster 1, H3g −2.0 0.0002008
5 NM_012074 DPF3 D4, zinc and double PHD fingers, family 3 −2.0 0.0000953
6 NM_018193 FANC1 Fanconi anemia, complementation group 1 −2.0 0.0026856
7 NM_052917 GALNT13 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 13 (GalNAc-T13) −2.0 0.0008409
8 NM_152754 SEMA3D Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semapborin) 3D −2.0 0.0021798
9 NM_032117 MND1 Meiotic nuclear divisions 1 homolog (S. cerevisiae) −2.0 0.0035557
10 NM_000059 BRCA2 Breast cancer 2, early onset −2.0 0.0049817
11 NM_006079 CITED2 Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 −2.0 0.0016884
12 NM_002192 INHBA Inhibin, beta A −2.0 0.0001218
13 NM_033518 SLC38A5 Solute carrier family 38, member 5 −2.0 0.0003078
14 NM_005239 ETS2 V-ets erythroblastosis virus E26 oncogene homolog 2 (avian) −2.0 0.0000035
15 NM_001039841 ARHGAP11B Rho GTPase activating protein 11B −2.1 0.0002937
16 NM_016426 GTSE1 G-2 and S-phase expressed 1 −2.1 0.0008579
17 NM_022111 CLSPN Claspin homolog (Xenopus laevis) −2.1 0.0013778
18 NM_021968 HIST1H4J Histone cluster 1, H4j −2.1 0.0004086
19 BC067351 GUSBL1 Glucuronidase, beta-like 1 −2.1 0.0000052
20 NM_018353 C14orf106 Chromosome 14 open reading frame 106 −2.1 0.0021285
21 NM_001099293 KIF4B Kinesin family member 4B −2.1 0.0007975
22 NM_181802 UBE2C Ubiquitin-conjugating enzyme E2C −2.1 0.0016383
23 NM_014573 TMEM97 Transmembrane protein 97 −2.1 0.0004448
34 NM_182909 FILIP1L Filamin A interacting protein 1-like −2.1 0.0014915
35 NM_002823 PTMA Prothymosin, alpha (gene sequence 28) −2.1 0.0028224
36 NM_000956 PTGER2 Prostaglandin E receptor 2 (subtype EP2), 53kDa −2.1 0.0025474
37 NM_004817 TJP2 Tight junction protein 2 (zona occludens 2) −2.1 0.0000007
38 NM_007317 KIF22 Kinesin family member 22 −2.1 0.000031
39 NR_002562 SNORD28 Small nucleolar RNA, C/D box 28 −2.1 0.001433
40 NM_016095 GINS2 GINS complex subunit 2 (Psf2 homolog) −2.1 0.0018093
41 NM_007317 KIF22 Kinesin family member 22 −2.1 0.0000356
42 NM_004731 SLC16A7 Solute carrier family 16, member 7 (monocarboxylic acid transporter 2) −2.1 0.0000023
43 NM_005496 SMC4 Structural maintenance of chromosomes 4 −2.1 0.0004444
44 NM_144586 LYPD1 LY6/PLAUR domain containing 1 −2.1 0.0005818
45 NM_001129 AEBP1 AE binding protein 1 −2.1 0.0000008
46 NM_014783 ARHGAP11A Rho GTPase activating protein 11A −2.1 0.0009603
47 NM_019035 PCDH18 Protocadherin 18 −2.1 0.000004
48 NM_013277 RACGAP1 Rac GTPase activating protein 1 −2.1 0.0006113
49 NM_006739 MCM5 Minichromosome maintenance complex component 5 −2.1 0.0002303
50 NM_152270 SLFN11 Schlafen family member 11 −2.1 0.0011236
51 NM_007243 NRM Nurim (nuclear envelope membrane protein) −2.2 0.000234
52 NM_007243 NRM Nurim (nuclear envelope membrane protein) −2.2 0.000234
53 NR_003125 LOC85391 RNA, small nucleolar −2.2 0.0004524
54 NM_182751 MCM10 Minichromosome maintenance complex component 10 −2.2 0.0041059
55 NM_001048201 UHRF1 Ubiquitin-like, containing PHD and RING finger domains, 1 −2.2 0.0001459
56 NM_014465 SULT1B1 Sulfotransferase family, cytosolic, 1B, member 1 −2.2 0.0065522
57 NM_002760 PRKY Protein kinase, Y-linked −2.2 0.0047595
58 NM_001827 CKS2 CDC28 protein kinase regulatory subunit 2 −2.2 0.0009191
59 NM_004772 C5orf13 Chromosome 5 open reading frame 13 −2.2 0.0006237
60 NM_005497 GJA7 Gap junction protein, alpha 7, 45kDa −2.2 0.0001851
61 NM_001744 CAMK4 Calcium/calmodulin-dependent protein kinase IV −2.2 0.0016928
62 NM_152495 CNIH3 Cornichon homolog 3 (Drosophila) −2.2 0.0032016
63 NM_006963 ZNF22 Zinc finger protein 22 (KOX 15) −2.2 0.0005145
64 NM_014363 SACS Spastic ataxia of Charlevoix-Saguenay (sacsin) −2.2 0.0000886
65 NM_018476 BEX1 Brain expressed, X-linked 1 −2.2 0.0043276
66 NM_006727 CDH10 Cadherin 10, type 2 (T2-cadherin) −2.2 0.0003019
67 NM_003545 HIST1H4E Histone cluster 1, H4e −2.2 0.0001393
68 NM_004415 DSP Desmoplakin −2.2 0.0000256
69 NM_001761 CCNF Cyclin F −2.2 0.0000636
70 NM_018101 CDCA8 Cell division cycle associated 8 −2.3 0.0015208
71 NM_021018 HIST1H3F Histone cluster 1, H3f −2.3 0.0038466
72 NM_004572 PKP2 Plakophilin 2 −2.3 0.0008219
73 NM_003517 HIST2H2AC Histone cluster 2, H2ac −2.3 0.0003061
74 NM_022908 NT5DC2 5′-nucleotidase domain containing 2 −2.3 0.0003366
75 NM_018410 DKFZp762E1312 Hypothetical protein DKFZp762E1312 −2.3 0.0010354
76 NM_024908 WDR76 WD repeat domain 76 −2.3 0.0029464
77 NM_004456 EZH2 Enhancer of zeste homolog 2 (Drosophila) −2.3 0.000033
78 NM_198433 AURKA Aurora kinase A −2.3 0.0009593
79 NM_001878 CRABP2 Cellular retinoic acid binding protein 2 −2.3 0.0003869
80 NM_014865 NCAPD2 Non-SMC condensin 1 complex, subunit D2 −2.3 0.0000146
81 NM_006479 RAD51AP1 RAD51 associated protein 1 −2.3 0.0004349
82 NM_003541 HIST1H4K Histone cluster 1, H4k −2.3 0.0001022
83 NM_005480 TROAP Trophinin associated protein (tastin) −2.3 0.0007361
84 NM_130398 EXO1 Exonuclease 1 −2.3 0.0007009
85 NM_003530 HIST1H3D Histone cluster 1, H3d −2.3 0.0000989
86 NM_012484 HMMR Hyaluronan-mediated motility receptor (RHAMM) −2.3 0.0010368
87 BX641032 WEE1 WEE1 homolog (S. pombe) −2.3 0.0020117
88 NM_005491 CXorf6 Chromosome X open reading frame 6 −2.3 0.000069
89 NM_004900 APOBEC3B Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B −2.3 0.002503
90 NM_020890 KIAA1524 KIAA1524 −2.4 0.0035147
91 NM_012177 FBXO5 F-box protein 5 −2.4 0.0029497
92 ENST00000377738 KRTAP2-4 Keratin associated protein 2-4 (KRTAP2-4), mRNA −2.4 0.0003921
93 NM_013230 CD24 CD24 molecule −2.4 0.0032149
94 NM_001813 CENPE Centromere protein E, 312kDa −2.4 0.0019189
95 NM_007174 CIT Citron (rho-interacting, serine/threonine kinase 21) −2.4 0.0000603
96 NM_002106 H2AFZ H2A histone family, member Z −2.4 0.0010744
97 NM_003524 HIST1H2BH Histone cluster 1, H2bh −2.4 0.0001753
98 NM_003784 SERPINB7 Serpin peptidase inhibitor, clade B (ovalbumin), member 7 −2.4 0.0011738
99 NM_017669 ERCC6L Excision repair cross-complementing rodent repair deficiency, complementation group 6-like −2.4 0.0037181
100 ENST00000377738 KRTAP2-4 Keratin associated protein 2-4 (KRTAP2-4), mRNA −2.4 0.0006498
101 ENST00000377738 KRTAP2-4 Keratin associated protein 2-4 (KRTAP2-4), mRNA −2.4 0.0006498
102 NM_021052 HIST1H2AE Histone cluster 1, H2ae −2.4 0.0004919
103 NM_002263 KIFC1 Kinesin family member C1 −2.4 0.002479
104 NM_003258 TK1 Thymidine kinase 1, soluble −2.4 0.0006185
105 NM_001048198 SNHG3-RCC1 Regulator of chromosome, condensation 1 −2.4 0.0000584
106 NM_013296 GPSM2 G-protein signaling modulator 2 (AGS3-like, C. elegans) −2.4 0.0006993
107 NM_031217 KIF18A Kinesin family member 18A −2.5 0.0001562
108 NM_001017420 ESCO2 Establishment of cohesion 1 homolog 2 (S. cerevisiae) −2.5 0.0013571
109 NM_014264 PLK4 Polo-like kinase 4 (Drosophila) −2.5 0.0031529
110 ENST00000302536 KIAA1576 KIAA1576 protein (KIAA1576), mRNA −2.5 0.0000329
111 NM_031966 CCNB1 Cyclin B1 −2.5 0.0000813
112 NM_003877 SOCS2 Suppressor of cytokine signaling 2 −2.5 0.0000898
113 NM_005325 HIST1HIA Histone cluster 1, H1a −2.5 0.0000106
114 NM_138555 KIF23 Kinesin family member 23 −2.5 0.0005602
115 NM_001012507 C6orf173 Chromosome 6 open reading frame 173 −2.5 0.0003908
116 NM_002466 MYBL2 V-myb mycloblastosis viral oncogene homolog (avian)-like 2 −2.5 0.0000271
117 NM_013372 GREM1 Gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis) −2.5 0.000007
118 NM_003529 HIST1H3A Histone cluster 1, H3a −2.5 0.0012216
119 NM_001034 RRM2 Ribonucleotide reductase M2 polypeptide −2.5 0.0034171
120 NM_000599 IGFBP5 Insulin-like growth factor binding protein 5 −2.6 0.0039748
121 NM_001033049 ADARB1 Adenosine deaminase, RNA-specific, B1 (RED1 homolog rat) −2.6 0.0000097
122 NM_000561 GSTM1 Glutathione S-transferase M1 −2.6 0.0003801
123 NM_005517 HMGN2 High-mobility group nucleosomal binding domain 2 −2.6 0.0001929
124 NM_175065 HIST2H2AB Histone cluster 2, H2ab −2.6 0.0001294
125 NM_006682 FGL2 Fibrinogen-like 2 −2.6 0.0004615
126 NM_001012410 SGOL1 Shugoshin-like 1 (S. pombe) −2.6 0.0072724
127 NM_003544 HIST1H4B Histone cluster 1, H4b −2.6 0.0001657
128 NM_153262 SYT14 Synaptotagmin XIV −2.6 0.0000915
129 NM_002263 KIFC1 Kinesin family member C1 −2.7 0.0013435
130 NM_182705 FAM101B Family with sequence similarity 101, member B −2.7 0.0000477
131 NM_006558 KHDRBS3 KH domain containing, RNA binding, signal transduction associated 3 −2.7 0.0000787
132 NM_001943 DSG2 Desmoglein 2 −2.7 0.0000628
133 NM_015975 TAF9B TAF9B RNA polymerase II, TATA box binding protein (TBP)-associated factor, 31kDa −2.7 0.0001503
134 NM_016591 GCNT4 Glucosaminyl (N-acetyl) transferase 4, core 2 (beta-1,6-N-acetylglucosaminyltransferase) −2.7 0.0002032
135 NM_014875 KIF14 Kinesin family member 14 −2.7 0.0026412
136 BX641032 WEE1 WEE1 homolog (S. pombe) −2.7 0.0018471
137 NM_016588 NRN1 Neuritin 1 −2.7 0.0000023
138 NM_003546 HIST1H4L Histone cluster 1, H4l −2.7 0.0012995
139 NM_006845 KIF2C Kinesin family member 2C −2.7 0.0020828
140 NR_002612 DLEU2 Deleted in lymphocytic leukemia, 2 −2.7 0.0017015
141 NM_031299 CDCA3 Cell division cycle associated 3 −2.7 0.0002869
142 NM_018849 ABCB4 ATP-binding cassette, sub-family B (MDR/TAP), member 4 −2.8 0.000121
143 NM_001067 TOP2A Topoisomerase (DNA) II alpha 170kDa −2.8 0.0004533
144 NM_020242 KIF15 Kinesin family member 15 −2.8 0.0002493
145 NM_004439 EPHA5 EPH receptor A5 −2.8 0.0000033
146 NM_003981 PRC1 Protein regulator of cytokinesis 1 −2.8 0.0054775
147 NM_002398 MEIS1 Meis homeobox 1 −2.8 0.0003329
148 NM_173084 TRIM59 Triparite motif-containing 59 −2.8 0.001123
149 NM_003533 HIST1H31 Histone cluster 1, H3i −2.8 0.0000119
150 NM_145061 C13orf3 Chromosome 13 open reading frame 3 −2.8 0.0003047
151 NM_001786 CDC2 Cell division cycle 2, G1 to S and G2 to M −2.8 0.0035238
152 NM_006101 NDC80 NDC80 homolog, kinetochore complex component (S. cerevisiae) −2.9 0.0012085
153 NM_012112 TPX2 TPX2, microtubule-associated, homolog (Xenopus laevis) −2.9 0.0000403
154 NM_016359 NUSAP1 Nucleolar and spindle associated protein 1 −2.9 0.0011078
155 NM_003540 HIST1H4F Histone cluster 1, H4f −2.9 0.0010387
156 NM_015341 NCAPH Non-SMC condensin 1 complex, subunit H −2.9 0.0003153
157 NM_012310 KIF4A Kinesin family member 4A −2.9 0.0001634
158 NM_001211 BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) −2.9 0.0000898
159 NM_003522 HIST1H2BF Histone cluster 1, H2bf −2.9 0.0011487
160 NM_152515 CKAP2L Cytoskeleton associated protein 2-like −3.0 0.0008625
161 NM_152562 CDCA2 Cell division cycle associated 2 −3.0 0.0001478
162 NM_178229 IQGAP3 IQ motif containing GTPase activating protein 3 −3.0 0.0006081
163 NM_001884 HAPLN1 Hyaluronan and proteoglycan link protein 1 −3.0 0.0003171
164 NR_001544 CYorf14 Chromosome Y open reading frame 14 −3.0 0.0001937
165 NM_022346 NCAPG Non-SMC condensin 1 complex, subunit G −3.0 0.0016196
166 NM_002867 RAB3B RAB3B, member RAS oncogene family −3.0 0.0000771
167 NM_001080480 MBOAT1 Membrane bound O-acyltransferase domain containing 1 −3.1 0.0000156
168 NM_006350 FST Follistatin −3.1 0.0008267
169 ENST00000389239 FAM64A Family with sequence similarity 64, member A (FAM64A), mRNA −3.1 0.0003557
170 NM_020675 SPC25 SPC25, NDC80 kinetochore complex component, homolog (S. cerevisiae) −3.1 0.0024131
171 NM_170589 CASC5 Cancer susceptibility candidate 5 −3.1 0.0006033
172 NM_002497 NEK2 NIMA (never in mitosis gene a)-related kinase 2 −3.1 0.0035344
173 NM_004701 CCNB2 Cyclin B2 −3.1 0.0006401
174 NM_003318 TTK TTK protein kinase −3.1 0.0011001
175 NM_002129 HMGB2 High-mobility group box 2 −3.1 0.0003609
176 NM_018131 CEP55 Centrosomal protein 55kDa −3.1 0.0053938
177 NM_003513 HIST1H2AB Histone cluster 1, H2ab −3.1 0.000027
178 NM_001032283 TMPO Thymopoietin −3.2 0.0003481
179 NM_001255 CDC20 Cell division cycle 20 homolog (S. cerevisiae) −3.2 0.0000258
180 NM_001711 BGN Biglycan −3.2 0.0000375
181 NM_001071 TYMS Thymidylate synthetase −3.2 0.0032506
182 NM_004934 CDH18 Cadherin 18, type 2 −3.2 0.0000862
183 NM_018136 ASPM Asp (abnormal spindle) homolog, microcephaly associated (Drosophila) −3.2 0.0001314
184 NM_020859 SHROOM3 Shroom family member 3 −3.2 0.0002947
185 NM_006147 IRF6 Interferon regulatory factor 6 −3.2 0.0002558
186 NM_018685 ANLN Anillin, actin binding protein −3.2 0.0004383
187 NM_005321 HIST1H1E Histone cluster 1, H1e −3.3 0.0000589
188 NM_017779 DEPDC1 DEP domain containing 1 −3.3 0.0005434
189 NM_002783 PSG7 Pregnancy specific beta-1-glycoprotein 7 −3.3 0.0002987
190 NM_005556 KRT7 Keratin 7 −3.4 0.0000318
191 NM_005322 HIST1H1B Histone cluster 1, H1b −3.4 0.000073
192 NM_014736 KIAA0101 KIAA0101 −3.4 0.0073048
193 NM_202002 FOXM1 Forkhead box M1 −3.4 0.0009265
194 NM_005030 PLK1 Polo-like kinase 1 (Drosophila) −3.4 0.0000316
195 NM_006461 SPAG5 Sperm associated antigen 5 −3.4 0.0002157
196 NM_016343 CENPF Centromere protein F, 350/400ka (mitosin) −3.5 0.0053205
197 NM_000609 CXCL12 Chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1) −3.5 0.0000196
198 NM_018689 KIAA1199 KIAA1199 −3.6 0.0000461
199 NM_145697 NUF2 NUF2, NDC80 kinetochore complex component, homolog (S. cerevisiae) −3.6 0.0008586
200 NM_005573 LMNB1 Lamin B1 −3.7 0.0000014
201 NM_203401 STMN1 Stathmin 1/oncoprotein 18 −3.8 0.0000397
202 NM_006013 RPL10 Ribosomal protein L10 −3.8 0.0000282
203 NM_014750 DLG7 Discs, large homolog 7 (Drosophila) −3.9 0.0004194
204 NM_003638 ITGA8 Integrin, alpha 8 −4.0 0.0005969
205 NM_003537 HIST1H3B Histone cluster 1, H3b −4.0 0.0033207
206 NM_014932 NLGN1 Neuroligin 1 −4.2 0.0048918
207 NR_003106 PWCR1 Prader-Willi syndrome chromosome region 1 −4.2 0.0041387
208 NM_002276 KRT19 Keratin 19 −4.2 0.0002805
209 NM_005733 KIF20A Kinesin family member 20A −4.3 0.005152
210 NM_001290 LDB2 LIM domain binding 2 −4.4 0.0000202
211 NM_001080428 ODZ2 Odz, odd Oz/ten-m homolog 2 (Drosophila) −4.5 0.0001199
212 NM_003521 HIST1H2BM Histone cluster 1, H2bm −4.5 0.0000106
213 NM_018284 GBP3 Guanylate binding protein 3 −4.6 0.0002522
214 NM_013381 TRHDE Thyrotropin-releasing hormone degrading enzyme −4.7 0.0001288
215 NM_001040152 PEG10 Paternally expressed 10 −4.7 0.0000323
216 NM_005159 ACTC1 Actin, alpha, cardiac muscle 1 −4.7 0.0000545
217 NM_003542 HIST1H4C Histone cluster 1, H4c −5.2 0.0002514
218 NM_022350 LRAP Leukocyte-derived arginine aminopeptidase −5.2 0.0000817
219 NM_002421 MMP1 Matrix metallopeptidase 1 (interstitial collagenase) −5.5 0.0047864
220 NM_002781 PSG5 Pregnancy specific beta-1-glycoprotein 5 −5.6 0.0000083
221 NM_005711 EDIL3 EGF-like repeats and discoidin 1-like domains 3 −6.5 0.0000014
222 NM_003411 ZFY Zinc finger protein, Y-linked −6.5 0.0000338
223 NM_005434 MALL Mal, T-cell differentiation protein-like −7.5 0.0000132
224 NM_004653 JARID1D Jumonji, AT rich interactive domain 1D −9.0 0.0000055
225 NM_001005852 CYorf15A Chromosome Y open reading frame 15A −9.7 0.0000309
226 NM_004932 CDH6 Cadherin 6, type 2, K-cadherin (fetal kidney) −10.2 0.0000005
227 NM_032576 CYorf15B Chromosome Y open reading frame 15B −11.1 0.0000012
228 NM_007125 UTY Ubiquitously transcribed tetratricopeptide repeat gene, Y-linked −11.2 0.0000027
229 NM_014893 NLGN4Y Neuroligin 4, Y-linked −11.8 0.0001143
230 NM_021013 KRT34 Keratin 34 −12.1 0.0000017
231 NM_004654 USP9Y Ubiquitin specific peptidase 9, Y-linked (fat facets-like, Drosophila) −16.3 0.0000009
232 NM_005045 RELN Reelin −17.4 0.0001692
233 NM_004681 EIF1AY Eukaryotic translation initiation factor 1A, Y-linked −19.5 0.0014353
234 NM_001008 RPS4Y1 Ribosomal protein S4, Y-linked 1 −27.2 0.0000016
235 NM_001999 FBN2 Fibrillin 2 (congenital contractural arachnodactyly) −47.8 0.0000903
236 NM_004660 DDX3Y DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked −59.9 0.0002855
Figure 2.
 
Relative quantification of 10 representative genes identified in the microarray. (A) RT-PCR was performed, and amplification products were subjected to agarose gel electrophoresis and were stained with ethidium bromide. (B) Each group was represented by two different cases whose RNA was pooled (sample pairs 1 and 2). Relative mRNA expression levels were normalized against β-actin. (C) Western blot analysis was performed using heterozygous GCD II, homozygous GCD II, and wild-type PCFs. (D) Each group was represented by two different cases whose protein was pooled (sample pairs 2 and 3). Relative protein expression levels were normalized to β-actin. Antibodies used are indicated to the left of each blot. WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Figure 2.
 
Relative quantification of 10 representative genes identified in the microarray. (A) RT-PCR was performed, and amplification products were subjected to agarose gel electrophoresis and were stained with ethidium bromide. (B) Each group was represented by two different cases whose RNA was pooled (sample pairs 1 and 2). Relative mRNA expression levels were normalized against β-actin. (C) Western blot analysis was performed using heterozygous GCD II, homozygous GCD II, and wild-type PCFs. (D) Each group was represented by two different cases whose protein was pooled (sample pairs 2 and 3). Relative protein expression levels were normalized to β-actin. Antibodies used are indicated to the left of each blot. WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Differential Expression of ECM-Associated Genes
To confirm the ECM affinity data, we next tested the expression of proteins involved in ECM remodeling by Western blot (Figs. 2C, 2D), as we expected that expression levels between wild-type, heterozygous, and homozygous GCD II PCFs would be different. We first investigated the expression patterns of collagen metabolism–related matrix metalloprotease (MMP)-1 and -2, because microarray assay profiles have shown a different expression of MMP-1 and -2. The protein levels of MMP-1 and -2 increased in heterozygous and homozygous GCD II compared with wild-type PCFs (Figs. 2C, 2D). Expression level of integrin α2, which is involved in collagen metabolism and cell adhesion, was also increased in heterozygous and homozygous GCD II PCFs. Furthermore, significantly increased protein levels of TGF-β receptors I, II, and III were observed in heterozygous and homozygous GCD II PCFs (Figs. 2C, 2D). These results suggest that the disturbance of ECM metabolism, especially collagen metabolism, is a major factor leading to TGFBIp deposition in corneal ECM of GCD II. 
Increased Affinities for ECM Substrates of GCD II PCFs
We detected altered expression of several ECM component genes (Table 3) in wild-type versus GCD II PCFs. As such, we hypothesized that the adhesive properties of GCD II PCFs may be different from those of wild-type PCFs. To test this, we investigated ECM adhesive properties of GCD II PCFs using an adhesion assay (Cytomatrix; Chemicon International), as described in Materials and Methods. The heterozygous and homozygous GCD II PCFs were more adhesive to collagen-I, collagen-IV, fibronectin, and lamine, than were the wild-type cells (Fig. 3). 
Figure 3.
 
Cell adhesion profiles of heterozygous GCD II, homozygous GCD II, and wild-type PCFs. Each column represents the mean value of four microspots; error bar, SD. PCF attachment experiments were performed with different ECM proteins. The experiment was repeated three times. The results are expressed as the mean ± SD (n = 3). BSA, bovine serum albumin; Col-I, type I collagen; Col-IV, type IV collagen; FN, fibronectin; LN, laminin; TN, tenascin; VN, vitronectin; WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Figure 3.
 
Cell adhesion profiles of heterozygous GCD II, homozygous GCD II, and wild-type PCFs. Each column represents the mean value of four microspots; error bar, SD. PCF attachment experiments were performed with different ECM proteins. The experiment was repeated three times. The results are expressed as the mean ± SD (n = 3). BSA, bovine serum albumin; Col-I, type I collagen; Col-IV, type IV collagen; FN, fibronectin; LN, laminin; TN, tenascin; VN, vitronectin; WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Discussion
In this study, cDNA microarray technology was used to compare the gene expression profiles of homozygous GCD II PCFs to that of wild-type cells, in an attempt to better understand a potential mechanism of GCD II disease. We detected at least a twofold change in expression of 555 genes and confirmed the relative expression levels of a select number of genes by RT-PCR and Western blot analysis. Finally, differences in the cell adhesion properties between GCD II and wild-type PCFs were detected, suggesting that disturbances in ECM-cell adhesion may play an important role in this disease. 
Expression Levels of Genes Involved in the TGF-β Signaling Pathway
The TGF-β signaling pathway has been implicated as a regulator in numerous cellular and physiological processes including ECM homeostasis. 16 The expression of TGF-β in corneal fibroblast cultures also suggests that it plays a role in regulating ECM metabolism through the TGF-β signaling pathway. 1719 TGF-β initiates signaling through a complex made up of TGF-β receptor (TβR) I and TβRII 20 and signals to the nucleus through the Smads protein. 21 Our results show that TβRI, -II, and -III were upregulated in heterozygous and homozygous GCD II PCFs compared with wild-type. Moreover, we identified different gene expression levels of the TβR complex assembly gene (FMOD; 3.2-fold increased, P < 0.0000113) in homozygous GCD II PCFs compared with wild-type PCFs (Table 4). This suggests that TGFBIp expression may occur more rapidly in GCD II than in wild-type PCFs under various physiological conditions and could result in accelerated TGFBIp deposition and ultimate GCD II disease. Also, because overexpression of misfolded or mutant proteins could induce protein aggregation or deposition, increased TβR expressions may play an important role in exacerbating GCD II pathogenesis. This idea is supported by previous studies in which GCD II was aggravated by TGF-β after LASIK surgery. 11,12,22 However, the specific mechanism(s) regarding the increase in TβR expression in GCD II corneal fibroblasts remains unknown. 
Differential Expression of Proteolytic Enzymes Involved in ECM Metabolism
TβR-mediated signaling stimulates matrix deposition by promoting the expression of components of the ECM such as collagen and suppresses and/or activates proteolytic enzymes such as MMPs, which also degrade collagen. 23,24 Previous studies have shown that expression of abnormal proteoglycan filaments and disruption in collagen organization were present among stromal TGFBIp deposits. 25 These studies suggest that altered ECM proteolytic enzyme activities affect TGFBIp deposits by degrading ECM molecules, by either scission of covalent bonds or cleavage of mutant TGFBIp. Several investigations suggest that abnormal proteolysis is involved in deposits of TGFBIp in the cornea of the TGFBI gene associated with corneal dystrophy. 26 This finding is consistent with the fact that amyloid precursor proteins associated with other amyloid diseases generally undergo proteolysis during amyloid generation. Such proteins include gelsolin in both lattice corneal dystrophy type I and Finnish-type familial amyloidosis, 27,28 amyloid β precursor protein in familial Alzheimer's disease, 29,30 and BRI2 in familial British dementia. 31,32 Our microarray data show differential expression of endopeptidase-related genes such as serine-type endopeptidase activity–related genes, serine-type endopeptidase inhibitor–related genes, aspartic-type endopeptidase activity, and metalloendopeptidase activity–related genes. Although ECM proteolytic enzymes such as MMPs for TGFBIp remain unidentified, our data suggest that proteolytic enzymes associated with ECM turnover may be involved in the generation of TGFBIp deposits in GCD II. Further studies are needed to identify specific proteolytic enzymes responsible for TGFBIp deposits in the cornea. 
Cell Adhesion and Integrin Signaling
TGFBIp contains a domain rich in cysteine residues (EMI domain), four highly conserved fasciclin-like (FAS) domains, and a COOH-terminal Arg-Gly-Asp (RGD) motif. The presence of the FAS domains and the RGD motif suggests that TGFBIp may play a functional role in cell adhesion. More recently, it was found that TGFBIp plays an inhibitory role in the attachment of human scleral fibroblasts to collagen type I through interaction with both αvβ3 and αvβ5 integrin receptors. 33 In the present investigation, we showed that heterozygous and homozygous GCD II PCFs tightly attached to collagen-I, collagen-IV, fibronectin, and lamine, compared with wild-type cells. These results support those in previous studies that show that TGFBIp plays a functional role in cell–ECM adhesion in the corneal stroma. However, our data suggest that tight attachment of heterozygous and homozygous GCD II PCFs to some ECM molecules is not due to a direct interaction between TGFBIp and the ECM. There are at least two possible explanations for this observation. First, TGFBIp expression was not significantly different in the heterozygous GCD II, homozygous GCD II, and wild-type PCFs. 15 Second, although TGFBIp can bind to collagens I, II, and III 34 and to fibronectin, 35 mutations in the TGFBI that commonly occur in certain corneal dystrophies do not apparently affect its binding to type I collagen, fibronectin, and laminin. 36 It is possible that signaling through integrins is involved in the attachment of GCD II PCFs to the ECM, especially since TGFBIp directly interacts with integrins. 37 This possibility is supported by the fact that increased integrin α2 expression was detected in heterozygous and homozygous GCD II PCFs. Therefore, we suggest that increased cell adhesion does not result from structural changes, as a result of mutation, in the RGD motif and FAS domain of TGFBIp, but rather because of downstream signaling events that occur as a result of interactions between integrins and mutant TGFBIp. 
In conclusion, our data suggest that the altered receptor–mediated signaling pathway of TGF-β and integrins play a key role in GCD II pathophysiology. This study also identified other novel factors involved in this process that could aid in the design of future experiments to further investigate the development of this disease. 
Footnotes
 Supported by Grant A080320 from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea.
Footnotes
 Disclosure: S. Choi, None; Y.-M. Yoo, None; B.-Y. Kim, None; T. Kim, None; H. Cho, None; S. Ahn, None; H.K. Lee, None; H.-S. Cho, None; E.K. Kim, None
The authors thank Mi-Na Park (Seoul National University, Seoul, Korea) for valuable discussions and Jung Wang Rim (DNALink, Inc., Seoul, Korea) for technical assistance. 
References
Skonier J Neubauer M Madisen L Bennett K Plowman GD Purchio AF . cDNA cloning and sequence analysis of beta ig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-beta. DNA Cell Biol. 1992;11:511–522. [CrossRef] [PubMed]
Klintworth GK . Advances in the molecular genetics of corneal dystrophies. Am J Ophthalmol. 1999;128:747–754. [CrossRef] [PubMed]
LeBaron RG Bezverkov KI Zimber MP Pavelec R Skonier J Purchio AF . Beta IG-H3, a novel secretory protein inducible by transforming growth factor-beta, is present in normal skin and promotes the adhesion and spreading of dermal fibroblasts in vitro. J Invest Dermatol. 1995;104:844–849. [CrossRef] [PubMed]
Billings PC Herrick DJ Kucich U . Extracellular matrix and nuclear localization of beta ig-h3 in human bladder smooth muscle and fibroblast cells. J Cell Biochem. 2000;79:261–273. [CrossRef] [PubMed]
Kim JE Jeong HW Nam JO . Identification of motifs in the fasciclin domains of the transforming growth factor-beta-induced matrix protein betaig-h3 that interact with the alphavbeta5 integrin. J Biol Chem. 2002;277:46159–46165. [CrossRef] [PubMed]
Zhang Y Wen G Shao G . TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res. 2009;69:37–44. [CrossRef] [PubMed]
Moon JW Kim SW Kim TI Cristol SM Chung ES Kim EK . Homozygous granular corneal dystrophy type II (Avellino corneal dystrophy): natural history and progression after treatment. Cornea. 2007;26:1095–1100. [CrossRef] [PubMed]
Cintron C Schneider H Kublin C . Corneal scar formation. Exp Eye Res. 1973;17:251–259. [CrossRef] [PubMed]
Cintron C Kublin CL . Regeneration of corneal tissue. Dev Biol. 1977;61:346–357. [CrossRef] [PubMed]
Takacs L Csutak A Balazs E Berta A . Immunohistochemical detection of betaIG-H3 in scarring human corneas. Graefes Arch Clin Exp Ophthalmol. 1999;237:529–534. [CrossRef] [PubMed]
Wan XH Lee HC Stulting RD . Exacerbation of Avellino corneal dystrophy after laser in situ keratomileusis. Cornea. 2002;21:223–226. [CrossRef] [PubMed]
Jun RM Tchah H Kim TI . Avellino corneal dystrophy after LASIK. Ophthalmology. 2004;111:463–468. [CrossRef] [PubMed]
Morand S Buchillier V Maurer F . Induction of apoptosis in human corneal and HeLa cells by mutated BIGH3. Invest Ophthalmol Vis Sci. 2003;44:2973–2979. [CrossRef] [PubMed]
Bustamante M Tasinato A Maurer F . Overexpression of a mutant form of TGFBI/BIGH3 induces retinal degeneration in transgenic mice. Mol Vis. 2008;14:1129–1137. [PubMed]
Choi SI Kim TI Kim KS . Decreased catalase expression and increased susceptibility to oxidative stress in primary cultured corneal fibroblasts from patients with granular corneal dystrophy type II. Am J Pathol. 2009;175:1–14. [CrossRef]
O'Kane S Ferguson MW . Transforming growth factor beta s and wound healing. Int J Biochem Cell Biol. 1997;29:63–78. [CrossRef] [PubMed]
Brown CT Applebaum E Banwatt R Trinkaus-Randall V . Synthesis of stromal glycosaminoglycans in response to injury. J Cell Biochem. 1995;59:57–68. [CrossRef] [PubMed]
Hayashi K Frangieh G Wolf G Kenyon KR . Expression of transforming growth factor-beta in wound healing of vitamin A-deficient rat corneas. Invest Ophthalmol Vis Sci. 1989;30:239–247. [PubMed]
Wilson SE He YG Lloyd SA . EGF, EGF receptor, basic FGF, TGF beta-1, and IL-1 alpha mRNA in human corneal epithelial cells and stromal fibroblasts. Invest Ophthalmol Vis Sci. 1992;33:1756–1765. [PubMed]
Blobe GC Schiemann WP Lodish HF . Role of transforming growth factor beta in human disease. N Engl J Med. 2000;342:1350–1358. [CrossRef] [PubMed]
Monteleone G Kumberova A Croft NM McKenzie C Steer HW MacDonald TT . Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest. 2001;108:601–609. [CrossRef] [PubMed]
Roh MI Grossniklaus HE Chung SH Kang SJ Kim WC Kim EK . Avellino corneal dystrophy exacerbated after LASIK: scanning electron microscopic findings. Cornea. 2006;25:306–311. [CrossRef] [PubMed]
Varga J Jimenez SA . Stimulation of normal human fibroblast collagen production and processing by transforming growth factor-beta. Biochem Biophys Res Commun. 1986;138:974–980. [CrossRef] [PubMed]
Overall CM Wrana JL Sodek J . Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem. 1989;264:1860–1869. [PubMed]
Akhtar S Meek KM Ridgway AE Bonshek RE Bron AJ . Deposits and proteoglycan changes in primary and recurrent granular dystrophy of the cornea. Arch Ophthalmol. 1999;117:310–321. [CrossRef] [PubMed]
Korvatska E Henry H Mashima Y . Amyloid and non-amyloid forms of 5q31-linked corneal dystrophy resulting from kerato-epithelin mutations at Arg-124 are associated with abnormal turnover of the protein. J Biol Chem. 2000;275:11465–11469. [CrossRef] [PubMed]
Huff ME Page LJ Balch WE Kelly JW . Gelsolin domain 2 Ca2+ affinity determines susceptibility to furin proteolysis and familial amyloidosis of finnish type. J Mol Biol. 2003;334:119–127. [CrossRef] [PubMed]
Page LJ Suk JY Huff ME . Metalloendoprotease cleavage triggers gelsolin amyloidogenesis. EMBO J. 2005;24:4124–4132. [CrossRef] [PubMed]
Thinakaran G Koo EH . Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008;283:29615–29619. [CrossRef] [PubMed]
Selkoe DJ . Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999;399:A23–31. [CrossRef] [PubMed]
Vidal R Frangione B Rostagno A . A stop-codon mutation in the BRI gene associated with familial British dementia. Nature. 1999;399:776–781. [CrossRef] [PubMed]
Choi SI Vidal R Frangione B Levy E . Axonal transport of British and Danish amyloid peptides via secretory vesicles. FASEB J. 2004;18:373–375. [PubMed]
Shelton L Summers-Rada J . Inhibition of human scleral fibroblast cell attachment to collagen type I by TGFBIp. Invest Ophthalmol Vis Sci. 2009;50(8):3542–3552. [CrossRef] [PubMed]
Hashimoto K Noshiro M Ohno S . Characterization of a cartilage-derived 66-kDa protein (RGD-CAP/beta ig-h3) that binds to collagen. Biochim Biophys Acta. 1997;1355:303–314. [CrossRef] [PubMed]
Billings PC Whitbeck JC Adams CS . The transforming growth factor-beta-inducible matrix protein (beta)ig-h3 interacts with fibronectin. J Biol Chem. 2002;277:28003–28009. [CrossRef] [PubMed]
Kim JE Park RW Choi JY . Molecular properties of wild-type and mutant betaIG-H3 proteins. Invest Ophthalmol Vis Sci. 2002;43:656–661. [PubMed]
Nam JO Kim JE Jeong HW . Identification of the alphavbeta3 integrin-interacting motif of betaig-h3 and its anti-angiogenic effect. J Biol Chem. 2003;278:25902–25909. [CrossRef] [PubMed]
Figure 1.
 
Gene ontological classification of differentially regulated genes in homozygous GCD II PCFs. Genes that were differentially expressed at a minimum of twofold were included in the analysis. Numbers in parentheses represent the number of genes.
Figure 1.
 
Gene ontological classification of differentially regulated genes in homozygous GCD II PCFs. Genes that were differentially expressed at a minimum of twofold were included in the analysis. Numbers in parentheses represent the number of genes.
Figure 2.
 
Relative quantification of 10 representative genes identified in the microarray. (A) RT-PCR was performed, and amplification products were subjected to agarose gel electrophoresis and were stained with ethidium bromide. (B) Each group was represented by two different cases whose RNA was pooled (sample pairs 1 and 2). Relative mRNA expression levels were normalized against β-actin. (C) Western blot analysis was performed using heterozygous GCD II, homozygous GCD II, and wild-type PCFs. (D) Each group was represented by two different cases whose protein was pooled (sample pairs 2 and 3). Relative protein expression levels were normalized to β-actin. Antibodies used are indicated to the left of each blot. WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Figure 2.
 
Relative quantification of 10 representative genes identified in the microarray. (A) RT-PCR was performed, and amplification products were subjected to agarose gel electrophoresis and were stained with ethidium bromide. (B) Each group was represented by two different cases whose RNA was pooled (sample pairs 1 and 2). Relative mRNA expression levels were normalized against β-actin. (C) Western blot analysis was performed using heterozygous GCD II, homozygous GCD II, and wild-type PCFs. (D) Each group was represented by two different cases whose protein was pooled (sample pairs 2 and 3). Relative protein expression levels were normalized to β-actin. Antibodies used are indicated to the left of each blot. WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Figure 3.
 
Cell adhesion profiles of heterozygous GCD II, homozygous GCD II, and wild-type PCFs. Each column represents the mean value of four microspots; error bar, SD. PCF attachment experiments were performed with different ECM proteins. The experiment was repeated three times. The results are expressed as the mean ± SD (n = 3). BSA, bovine serum albumin; Col-I, type I collagen; Col-IV, type IV collagen; FN, fibronectin; LN, laminin; TN, tenascin; VN, vitronectin; WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Figure 3.
 
Cell adhesion profiles of heterozygous GCD II, homozygous GCD II, and wild-type PCFs. Each column represents the mean value of four microspots; error bar, SD. PCF attachment experiments were performed with different ECM proteins. The experiment was repeated three times. The results are expressed as the mean ± SD (n = 3). BSA, bovine serum albumin; Col-I, type I collagen; Col-IV, type IV collagen; FN, fibronectin; LN, laminin; TN, tenascin; VN, vitronectin; WT, wild-type; HE, heterozygous GCD II; HO, homozygous GCD II. *P < 0.05.
Table 1.
 
Pairs of GCD II and Normal Samples
Table 1.
 
Pairs of GCD II and Normal Samples
Pair Normal Cornea Sex/Age Mean Age Heterozygous Sex/Age Mean Age Homozygous Sex/Age Mean Age Use of Samples
1 F/20 F/37 F/13 Microarray
RT-PCR
Western blot
Cell-adhesion assay
2 M/10 25.3 F/20 35.3 M/10 16.6 Microarray
RT-PCR
Cell-adhesion assay
3 M/45 F/49 F/27 Microarray
Cell-adhesion assay
Table 2.
 
PCR Primer Pairs
Table 2.
 
PCR Primer Pairs
Genes Accession Number Forward Primers Reverse Primers Product Size (bp) Annealing Temp. (°C)
FMOD NM_002023 5′-GGAAGAGGGGATCTTTGGAC-3′ 5′-CCACCACTCATGCTTTTCCT-3′ 199 60
SOD-2 NM_001024466 5′-CGTCACCGAGGAGAAGTACC-3′ 5′-CTGATTTGGACAAGCAGCAA-3′ 196 59
TGF1 NM_000660 5′-GGGACTATCCACCTGCAAGA-3′ 5′-CCTCCTTGGCGTAGTAGTCG-3′ 239 60
TGF2 NM_001135599 5′-CCGGAGGTGATTTCCATCTA-3′ 5′-CTCCATTGCTGAGACGTCAA-3′ 287 58
TGF3 NM_003239 5′-GAGTCAGAGCCCAGCAAAAC-3′ 5′-AGAAGGAGGGAGGAAAACCA-3′ 246 58
TGFB1 NM_000358 5′-GTGTGTGCTGTGCAGAAGGT-3′ 5′-TTGAGAGTGGTAGGGCTGCT-3′ 172 58
β-Actin NM_001101 5′-GGACTTCGAGCAAGAGATGG-3′ 5′-AGCACTGTGTTGGCGTACAG-3′ 234 58
Table 3.
 
GO Analysis of Genes Up- and Downregulated in GCD II CFBs
Table 3.
 
GO Analysis of Genes Up- and Downregulated in GCD II CFBs
GO ID GO Category Genes
Up Down n
GO:0007165 Signal transduction SFRP4, C3, GRP, TLR3 CXCL5, CXCL6, AHR, DTNA, CCL26, TNFAIP6, F2RL2, TAS2R43, GDF15, LPHN2, TNFRSF10A, TLR4, ANGPT1, TGFBR3, PTGER4, RASSF2, TLR1, ANK2, CLIC2, TNC, MAPK10, PBEF1, RAPH1, IRAK3 ARHGAP118, FGL2, PTGER2 ARHGAP11A, CAMK4, GPSM2, IGFBP5, CXCL12, TRHDE 37
GO:0007267 Cell-cell signaling IL8, MME, STC1, CXCL5, CXCL6, CCL2, CCL26, TNFAIP6, GDF15, EFNA5 LIF, PBEF1 INHBA, CXCL12, DLG7, TRHDE 15
GO:0007229 Integrin-mediated signaling pathway ITGB3 ITGA8 2
GO:0005615 Extracellular space SFRP4, SCG2, GRP, APOL1, IGFBP2, IL8, STC1, CXCL5, CXCL1, CXCL6, CCL2, CFH, CCL26, AKRIB1, CFHR1, MMP3, SULF2, APOD, CXCL2, LGALS3BP, CSF1, GDF15, GREM2, CLU, EFNA5, PLA2R1, WFDC1, LIF, PAPPA, TNFAIP2 BRCA2, GREM1, PSG7, CXCL12, MMP1, PSG5, RELN 37
GO:0030574 Collagen catabolism MMP3 MMP1 2
O:0001306 Response to oxidative stress SOD2, OSGIN2 2
GO:0007179 Transforming growth factor-beta receptor signaling pathway GDF15, TGFBR3 2
GO:0007155 Cell adhesion CLDN1, PCDHB3, CCL2 TNFAIP6, LGALS3BP, ROBO1, CNTNAP2, ITGB3, COL8A1, SRPX, ADAM23, RASSF2, HMCN1, TNC, LAMC2, CASK, THBS3, PCDHB13, NFASC AEBP1, PCDH18, TROAP, DSG2, HAPLN1, CDH18, CXCL12, NLGN1, EDIL3, CDH6, NLGN4Y, RELN 31
GO:0007156 Homophilic cell adhesion PCDHB3, ROBO1, PCDHB2 PCDHB4, PCDHB13 PCDH18, CDH10, DSG2, CDH18, CDH6 10
GO:0030155 Regulation of cell adhesion ICAM1, IL8, LAMA3 3
GO:0006955 Immune response IF16, OAS2, OAS1, IFI27, IFIT3, HLA-DPA1, IL8, CXCL5, CXCL1, CXCL6, DPP4, CCL26, IGJ, IFI30, CXCL2, PSMB9, ILIR1, TAP1, PTGER4, HLA-DPB1, MR1, LIF, HLA-E, HLA-C, MICA, IRF1, HLA-E, HLA-C, IFIT5, IFITM3, HLA-B, PSMB8, MICA, HLA-B, HLA-DPB1 EXO1, CXCL12, GBP3 37
GO:0006954 Inflammatory response C3, SCG2, IL8, TLR3, CXCL5 CXCL1, CXCL6, CCL2, CCL26, TNFAIP6, CXCL2, ILIR1, AOX1, TLR4, EPHX2, TLR1 CXCL12 17
GO:0006958 Complement activation, classic pathway C3, CIS, SERPING1, CF1, CLU 5
GO:0006956 Complement activation, classic pathway CFHR1, CFB 2
GO:0002474 Antigen processing and presentation of peptide antigen via MHC class I HLA-E, HLA-C, MICA, HLA-B, MICA, 5
GO:0019885 Antigen processing and presentation of endogenous ARTS-1 LRAP 2
GO:0030154 Cell differentiation SFRP4, FRZB, CSF1, TTLL7, DUSP6, EFNA5, FRK, PAPPA, DCLK1 SEMA3D, BEX1, CENPF, STMN1, ITGA8, PEG10 15
GO:0008283 Cell proliferation CREG1 KIF2C, KIF15, TPX2 8
GO:0008285 Negative regulation of cell proliferation IL8, CXCL1, RARRES3, FRK, GPNMB 5
GO:0005856 Cytoskeleton FRMD4B, PLEKHH2, FLG, EPB4IL5, MAP9, RAPH1 PKP2, DSG2, SHROOM3, ACTC1 10
GO:0005739 Mitochondrion IFI6, OAS2, OAS1, SOD2, AK3L1, ACSL5, PDK3, DMGDH, LACTB, BDH2, BNIP3, SQRDL KIAA0101 13
GO:0007049 Cell cycle PDPN, RASSF2, MAP9, MAPK13 SGOL2, FANC1, CDC2, CLSPN, CI4orf106, UBE2C, C1T, SMC4, RACGAP1, UHRF1, CKS2, CCNF, CDCA8, NCAPD2, WEE1, FBXO5, CENPE, ERCC6L, KIFC1, ESCO2, KIF23, SGOLI, KIFC1, CDCA3, PRC1, NDC80, NUSAP1, BUBIB, PLK1, CDCA2, NCAPG, FAM64A, SPC25, CCNB2, CEP55, CDC20, ASPM, ANLN, FOXM1, SPAG5, NUF2, DLG7 46
GO:0051318 G1 phase PRUNE2, PRUNE2 2
GO:0007601 Visual perception GLRB, HMCN1 GJA7 3
GO:0004252 Serine-type endopeptidase activity CFB, CORIN, PRSS23, CF1 RELN 5
GO:0004867 Serine-type endopeptidase inhibitor activity SERPING1, SERPIN11, WFDC1 SERPINB7 4
GO:0004190 Aspartic-type endopeptidase activity PEG10 1
GO:0004222 Metalloendopeptidase activity ADAM23 1
GO:0030574 Collagen catabolic process MMP3 MMP1 2
GO:0030199 Collagen fibrit organization COLI4A1 1
GO:0005581 Collagen COL14A1 1
GO:0004232 Interstitial collagenase activity MMP1 1
GO:0007181 Transforming growth factor beta receptor complex assembly FMOD 1
GO:0007179 Transforming growth factor-beta receptor signaling pathway GDF15, TGFBR3 2
GO:0030512 Negative regulation of transforming growth factor beta receptor signaling pathway PEG10 1
GO:0006512 Ubiquitin cycle FBXO32, FBXO16, FBXL2 UBE2C, UHRF1, FBXO5, CDCA3, CDC20, USP9Y 9
GO:0004842 Ubiquitin-protein ligase activity FBXL2 UBE2C 2
GO:0009611 Response to wounding F2RL2, GAP43 2
GO:0006979 Response to oxidative stress SOD2, PRNP 2
GO:0004364 Glutathione S-transferase activity GSTM1 1
Table 4.
 
Upregulated Homozygous GCD II–Related Genes
Table 4.
 
Upregulated Homozygous GCD II–Related Genes
No. Gene Accession Gene Symbol Gene Description Change P
1 NM_006820 IFI44L Interferon-induced protein 44-like 43.5 0.0017777
2 NM_022872 IFI6 Interferon, alpha-inducible protein 6 17.1 0.0002129
3 NM_003014 SFRP4 Secreted frizzled-related protein 4 16.5 0.0000311
4 NM_022783 DEPDC6 DEP domain containing 6 15.2 0.0000081
5 NM_000064 C3 Complement component 3 15.2 0.0000078
6 NM_002535 OAS2 2′-5′-Oligoadenylate synthetase 2, 69/71kDa 12.9 0.0006065
7 NM_017523 XAF1 XIAP associated factor-1 11.4 0.0005192
8 NM_152999 STEAP2 Six transmembrane epithelial antigen of the prostate 2 10.2 0.0000087
9 NM_021101 CLDN1 Claudin I 10.2 0.0002109
10 NM_016816 OAS1 2′,5′-Oligoadenylate synthetase 1, 40/46kDa 9.7 0.0035803
11 ENST00000260184 FLJ20035 Hypothetical protein FLJ20035 (FLJ20035), mRNA 9.7 0.0013714
12 NM_005532 IFI27 Interferon, alpha-inducible protein 27 9.1 0.0003262
13 NM_003469 SCG2 Secretogranin II (chromogranin C) 8.4 0.0000092
14 NM_002091 GRP Gastrin-releasing peptide 8.3 0.0000031
15 NM_001031683 IFIT3 Interferon-induced protein with tetratricopeptide repeats 3 7.6 0.0061816
16 uc002feh.1 CHST6 Carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6 7.6 0.0000052
17 NM_139072 DNER Delta/notch-like EGF repeat containing 7.5 0.0000055
18 NM_080284 ABCA6 ATP-binding cassette, sub-family A (ABC1), member 6 7.3 0.0000006
19 NM_203349 SHC4 SHC (Src homology 2 domain containing) family, member 4 7 0.0000941
20 NM_020299 AKRIBI0 Aldo-keto reductase family 1, member B10 (aldose reductase) 6.9 0.0000183
21 NM_007168 ABCA8 ATP-binding cassette, sub-family A (ABC1), member 8 6.7 0.0001116
22 NM_006417 IFI44 Interferon-induced protein 44 6.7 0.002165
23 NM_033554 HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 6.6 0.0000318
24 NM_024574 C4orf31 Chromosome 4 open reading frame 31 6.6 0.0000578
25 NM_145343 APOL1 Apolipoprotein L, 1 6.6 0.0001028
26 NM_033554 HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 6.5 0.0002743
27 NM_033554 HLA-DPA1 Major histocompatibility complex, class II, DP alpha 1 6.5 0.0002743
28 NR_003198 SNORD114-6 Small nucleolar RNA, C/D box 114-6 6.5 0.0000037
29 NM_000597 IGFBP2 Insulin-like growth factor binding protein 2, 36kDa 6.2 0.0005975
30 NM_004163 RAB27B RAB27B, member RAS oncogene family 6.1 0.0001163
32 NM_000201 ICAM1 Intercellular adhesion molecule I (CD54), human rhinovirus receptor 6 0.0000264
33 NM_000584 IL8 Interleukin 8 5.9 0.0001314
34 NM_021110 COL14A1 Collagen, type XIV, alpha I (undulin) 5.5 0.0000128
35 NM_001024465 SOD2 Superoxide dismutase 2, mitochondrial 5.5 0.0004007
38 NM_003265 TLR3 Toll-like receptor 3 5.3 0.0012359
39 NM_152703 SAMD9L Sterile alpha motif domain containing 9-like 5.1 0.0005941
40 NM_007288 MME Membrane metallo-endopeptidase 4.8 0.0000029
41 NM_005907 MAN1A1 Mannosidase, alpha, class IA, member 1 4.7 0.0000526
42 NM_003155 STC1 Stanniocalcin 1 4.7 0.0003264
43 NM_022154 SLC39A8 Solute carrier family 39 (zinc transporter), member 8 4.7 0.0034818
44 NM_139248 LIPH Lipase, member H 4.6 0.0000636
45 NM_001002264 EPSTI1 Epithelial stromal interaction I (breast) 4.6 0.0019874
46 BC022571 PRUNE2 Prune homolog 2 (Drosophila) 4.5 0.0006296
47 NM_002994 CXCL5 Chemokine (C-X-C motif) ligand 5 4.5 0.001963
48 NM_001511 CXCL1 Chemokine (C-X-C motif) ligand I (melanoma growth stimulating activity, alpha) 4.5 0.006012
49 NM_002538 OCLN Occludin 4.4 0.00084
50 NM_018937 PCDHB3 Protocadherin beta 3 4.4 0.0000115
51 NM_145172 WDR63 WD repeat domain 63 4.3 0.0000206
52 NM_004585 RARRES3 Retinoic acid receptor responder (tazarotene induced) 3 4.3 0.0002066
53 NM_003739 AKR1C3 Aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II) 4.3 0.0000081
54 NM_002993 CXCL6 Chemokine (C-X-C motif) ligand 6 (granulocyte chemotactic protein 2) 4.3 0.0004347
55 NM_016352 CPA4 Carboxypeptidase A4 4.3 0.0000333
56 NM_017554 PARP14 Poly (ADP-ribose) polymerase family, member 14 4.2 0.0019238
57 NM_002982 CCL2 Chemokine (C-C motif) ligand 2 4.2 0.0000148
58 NM_205845 AKR1C2 Aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-alpha hydroxysteroid dehydrogenase, type III) 4.2 0.0000279
59 NM_032812 PLXDC2 Plexin domain containing 2 4.1 0.0000003
60 NM_138818 PRUNE2 Prune homolog 2 (Drosophila) 4 0.0000703
61 NM_001935 DPP4 Dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2) 4 0.0000083
62 NM_001013442 EPGN Epithelial mitogen homolog (mouse) 3.9 0.0000298
63 NM_000186 CFH Complement factor H 3.9 0.0000126
64 NM_014314 DDX58 DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 3.8 0.0033267
65 NM_182767 SLC6A15 Solute carrier family 6, member 15 3.8 0.000131
66 NM_080671 KCNE4 Potassium voltage-gated channel, Isk-related family, member 4 3.7 0.0004738
67 NM_001390 DTNA Dystrobrevin, alpha 3.7 0.0000589
68 NM_175861 TMTC1 Transmembrane and tetratricopeptide repeat containing 1 3.7 0.0000083
69 NM_006072 CCL26 Chemokine (C-C motif) ligand 26 3.6 0.0000234
70 NM_144646 IGJ Immunoglobulin J polypeptide, linker protein for immunoglobulin alpha and mu polypeptides 3.6 0.0011411
71 NM_003851 CREG1 Cellular repressor of E1A-stimulated genes 1 3.6 0.0000007
72 NM_153703 PODN Podocan 3.6 0.0000006
73 NM_007115 TNFAIP6 Tumor necrosis factor, alpha-induced protein 6 3.6 0.0009063
74 NM_001628 AKR1B1 Aldo-keto reductase family 1, member B1 (aldose reductase) 3.5 0.000003
75 NM_016848 SHC3 SHC (Src homology 2 domain containing) transforming protein 3 3.5 0.000021
76 NM_018349 MCTP2 Multiple C2 domains, transmembrane 2 3.5 0.000013
77 NM_015123 FRMD4B FERM domain containing 4B 3.5 0.0000545
78 NM_015529 MOXD1 Monooxygenase, DBH-like 1 3.5 0.0000004
79 NM_198129 LAMA3 Laminin, alpha 3 3.5 0.0000003
80 NM_080283 ABCA9 ATP-binding cassette, sub-family A (ABC1), member 9 3.4 0.0002608
81 NM_000313 PROS1 Protein S (alpha) 3.4 0.0000002
82 NM_015028 TNIK TRAF2 and NCK interacting kinase 3.4 0.0016728
83 NM_004101 F2RL2 Coagulation factor II (thrombin) receptor-like 2 3.4 0.0000043
84 NM_017439 Icag7.1314 Hypothetical protein LOC54103 3.3 0.0007954
85 NM_005824 LRRC17 Leucine rich repeat containing 17 3.3 0.0000081
86 NM_001001924 MTUS1 Mitochondrial tumor suppressor 1 3.3 0.0002024
87 NM_006393 NEBL Nebulette 3.3 0.0000077
88 NM_176884 TAS2R43 Taste receptor, type 2, member 43 3.3 0.0015163
89 NM_000115 EDNRB Endothelin receptor type B 3.3 0.0010275
90 NM_153366 SVEP1 Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 3.2 0.0000004
91 NM_016246 HSD17B14 Hydroxysteroid (17-beta) dehydrogenase 14 3.2 0.0000521
92 NM_002023 FMOD Fibromodulin 3.2 0.0000113
93 NM_002113 CFHR1 Complement factor H-related 1 3.2 0.0004559
94 NM_024636 STEAP4 STEAP family member 4 3.2 0.0013693
95 NM_002422 MMP3 Matrix metallopeptidase 3 (stromelysin 1, progelatinase) 3.1 0.0000206
96 NM_018837 SULF2 Sulfatase 2 3.1 0.0000052
97 NM_017614 BHMT2 Betaine-homocysteine methyltransferase 2 3.1 0.0000017
98 NM_006332 IFI30 Interferon, gamma-inducible protein 30 3.1 0.0000761
99 NM_001463 FRZB Frizzled-related protein 3.1 0.0012231
100 NM_201442 C1S Complement component 1, s subcomponent 3.1 0.0000036
101 NM_058229 FBXO32 F-box protein 32 3.1 0.0000464
102 NM_001710 CFB Complement factor B 3.1 0.0011518
103 NM_173567 ABHD7 Abhydrolase domain containing 7 3.1 0.0016296
104 NM_001647 APOD Apolipoprotein D 3.0 0.0048695
105 NR_003578 ZNF702 Zinc finger protein 702 3.0 0.0003033
106 NM_006474 PDPN Podoplanin 3.0 0.0000074
107 NM_002089 CXCL2 Chemokine (C-X-C motif) ligand 2 3.0 0.0071753
108 NM_198520 C12orf63 Chromosome 12 open reading frame 63 3.0 0.0016097
109 NM_001012967 FLJ31033 Hypothetical protein FLJ31033 3.0 0.0010071
110 NM_018355 ZNF415 Zinc finger protein 415 3.0 0.0001087
111 NM_005103 FEZ1 Fasciculation and elongation protein zeta 1 (zygin 1) 2.9 0.0013669
112 NM_001030060 SAMD5 Sterile alpha motif domain containing 5 2.9 0.0003825
113 NM_000062 SERPING1 Serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, (angioedema, hereditary) 2.9 0.0017786
114 ENST00000326754 FLJ25801 Hypothetical protein FLJ25801 (FLJ25801), mRNA 2.9 0.00033
115 NM_001038628 B3GALNT1 Beta-1,3-N-acetylgalactosaminyltransferase 1 (globoside blood group) 2.9 0.000004
116 NM_005567 LGALS3BP Lectin, galactoside-binding, soluble, 3 binding protein 2.9 0.0004468
117 NM_000689 ALDH1A1 Aldehyde dehydrogenase 1 family, member A1 2.9 0.0019248
118 NM_000757 CSF1 Colony stimulating factor 1 (macrophage) 2.9 0.0000119
119 NM_004864 GDF15 Growth differentiation factor 15 2.9 0.0001212
120 NM_001710 CFB Complement factor B 2.9 0.0013733
121 NM_001013732 C6orf138 Chromosome 6 open reading frame 138 2.9 0.0005379
122 NM_012302 LPHN2 Latrophilin 2 2.8 0.0001229
123 NM_183376 ARRDC4 Arrestin domain containing 4 2.8 0.0000015
124 NM_007257 PNMA2 Paraneoplastic antigen MA2 2.8 0.0052895
125 ENST00000296529 TMEM144 Transmembrane protein 144 (TMEM144), mRNA 2.8 0.0056544
126 NM_052831 C6orf192 Chromosome 6 open reading frame 192 2.8 0.0000583
127 NM_004675 DIRAS3 DIRAS family, GTP-binding RAS-like 3 2.8 0.0000624
128 NM_172069 PLEKHH2 Pleckstrin homology domain containing, family H (with MyTH4 domain) member 2 2.8 0.0001397
129 NM_182969 XRRA1 X-ray radiation resistance associated 1 2.8 0.0000341
130 NM_018242 SLC47A1 Solute carrier family 47, member 1 2.8 0.0001539
131 NM_017549 EPDR1 Ependymin related protein 1 (zebrafish) 2.8 0.0000008
132 NM_203464 AK3L1 Adenylate kinase 3-like 1 2.8 0.0001709
133 NM_004827 ABCG2 ATP-binding cassette, sub-family G (WHITE), member 2 2.7 0.0000899
134 NM_003844 TNFRSF10A Tumor necrosis factor receptor superfamily, member 10a 2.7 0.0004671
135 NM_002222 ITPR1 Inositol 1,4,5-triphosphate receptor, type 1 2.7 0.0000039
136 NM_003543 HISTIH4H Histone cluster 1, H4h 2.7 0.0001016
137 NM_148954 PSMB9 Proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2) 2.7 0.003365
138 NM_148954 PSMB9 Proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2) 2.7 0.003365
139 NM_002800 PSMB9 Proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2) 2.7 0.003365
140 NM_021244 RRAGD Ras-related GTP binding D 2.7 0.0004553
141 NM_178826 TMEM16D Transmembrane protein 16D 2.6 0.0000977
142 NM_000877 IL1R1 Interleukin 1 receptor, type 1 2.6 0.0000427
143 NM_133631 ROBO1 Roundabout, axon guidance receptor, homolog 1 (Drosophila) 2.6 0.000011
144 NM_014141 CNTNAP2 Contactin associated protein-like 2 2.6 0.0000317
145 NM_001334 CTSO Cathepsin O 2.6 0.0000504
146 NM_001085423 C17orf60 Chromosome 17 open reading frame 60 2.6 0.0002676
147 NM_002045 GAP43 Growth associated protein 43 2.6 0.0000103
148 NM_024686 TTLL7 Tubulin tyrosine ligase-like family, member 7 2.6 0.0000499
149 NM_005502 ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1 2.6 0.0000177
150 NM_000593 TAP1 Transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) 2.6 0.0031895
151 NM_000593 TAP1 Transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) 2.6 0.0031895
152 NM_000593 TAP1 Transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) 2.6 0.0031895
153 NM_005779 LHFPL2 Lipoma HMG1C fusion partner-like 2 2.6 0.0001421
154 NM_007047 BTN3A2 Butyrophilin, subfamily 3, member A2 2.6 0.0000841
155 NM_012472 LRRC6 Leucine rich repeat containing 6 2.5 0.0006272
156 NM_001159 AOX1 Aldehyde oxidase 1 2.5 0.000033
157 NM_017734 PALMD Palmdelphin 2.5 0.0003744
158 NM_004170 SLC1A1 Solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 2.5 0.000006
159 NM_000311 PRNP Prion protein (p27-30) (Creutzfeldt-Jakob disease, Gerstmann-Strausler-Scheinker syndrome, fatal familial insomnia) 2.5 0
160 NM_005025 SERPINI1 Serpin peptidase inhibitor, clade 1.(neuroserpin), member 1 2.5 0.0001759
161 NM_001946 DUSP6 Dual specificity phosphatase 6 2.5 0.0000949
162 NM_000212 ITGB3 Integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) 2.5 0.0001519
164 NR_003530 MEG3 Maternally expressed 3 2.5 0.0001135
165 NM_015274 MAN2B2 Mannosidase, alpha, class 2B, member 2 2.5 0.0000109
166 NM_006207 PDGFRL Platelet-derived growth factor receptor-like 2.5 0.0001507
167 NM_000722 CACNA2D1 Calcium channel, voltage-dependent, alpha 2/delta subunit 1 2.5 0.0000006
168 NM_001975 ENO2 Enolase 2 (gamma, neuronal) 2.5 0.000141
169 NM_002637 PHKA1 Phosphorylase kinase, alpha 1 (muscle) 2.5 0.0000154
170 NM_022469 GREM2 Gremlin 2, cysteine knot superfamily, homolog (Xenopus laevis) 2.5 0.0000111
171 NM_001040458 ARTS-1 Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator 2.5 0.0000227
172 NM_001962 EFNA5 Ephrin-A5 2.5 0.0000425
173 NM_001850 COL8A1 Collagen, type VIII, alpha 1 2.5 0.0000884
174 NM_014367 C3orf28 Chromosome 3 open reading frame 28 2.5 0.0038544
175 NM_024621 VEPH1 Ventricular zone expressed PH domain homolog 1 (zebrafish) 2.5 0.000141
176 NM_017901 TPCN1 Two pore segment channel 1 2.5 0.0000426
177 NM_003551 NME5 Non-metastatic cells 5, protein expressed in (nucleoside-diphosphate kinase) 2.5 0.0014518
178 NM_203380 ACSL5 Acyl-CoA synthetase long-chain family member 5 2.5 0.004572
179 NM_007036 ESM1 Endothelial cell-specific molecule 1 2.5 0.0005156
180 NM_006587 CORIN Corin, serine peptidase 2.5 0.000425
181 NM_138554 TLR4 Toll-like receptor 4 2.5 0.0000129
182 NM_000187 HGD Homogentisate 1,2-dioxygenase (homogentisate oxidase) 2.4 0.000498
183 NM_000187 HGD Homogentisate 1,2-dioxygenase (homogentisate oxidase) 2.4 0.000498
184 NM_005391 PDK3 Pyruvate dehydrogenase kinase, isozyme 3 2.4 0.0017101
185 NM_173508 SLC35F3 Solute carrier family 35, member F3 2.4 0.0002497
186 NM_000147 FUCA1 Fucosidase, alpha-L-1, tissue 2.4 0.0001624
187 NM_181785 SLC46A3 Solute carrier family 46, member 3 2.4 0.0000173
188 NM_002031 FRK Fyn-related kinase 2.4 0.0002699
189 NM_206996 SPAG17 Sperm associated antigen 17 2.4 0.0002856
190 NM_006307 SRPX Sushi-repeat-containing protein, X-linked 2.4 0.0003416
191 NM_007366 PLA2R1 Phospholipase A2 receptor 1, 180kDa 2.4 0.000002
192 NM_020041 SLC2A9 Solute carrier family 2 (facilitated glucose transporter), member 9 2.4 0.0001373
193 NM_031419 NFKBIZ Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 2.4 0.0001795
194 NM_000214 JAG1 Jagged I (Alagille syndrome) 2.4 0.0004701
195 NM_001979 EPHX2 Epoxide hydrolase 2, cytoplasmic 2.4 0.0002466
196 NM_006095 ATP8A1 ATPase, aminophospholipid transporter (APLT), Class 1, type 8A, member 1 2.4 0.0000686
197 NM_053276 VIT Vitrin 2.4 0.0000835
198 NM_001146 ANGPT1 Angiopoietin 1 2.4 0.0003832
199 NM_001040457 RHBDD2 Rhomboid domain containing 2 2.4 0.0000221
200 NM_138287 DTX3L Deltex 3-like (Drosophila) 2.4 0.0052558
201 NM_003812 ADAM23 ADAM metallopeptidase domain 23 2.4 0.0000041
202 NM_006994 BTN3A3 Butyrophilin, subfamily 3, member A3 2.4 0.0003593
204 NM_018936 PCDHB2 Protocadherin beta 2 2.4 0.0002569
205 NM_015194 MYOID Myosin ID 2.4 0.0000391
206 NM_001086 AADAC Arylacetamide deacetylase (esterase) 2.3 0.0000226
207 NM_014467 SRPX2 Sushi-repeat-containing protein, X-linked 2 2.3 0.0000049
208 NM_024726 IQCA IQ motif containing with AAA domain 2.3 0.0001621
209 NM_002016 FLG Filaggrin 2.3 0.002256
210 NM_003243 TGFBR3 Transforming growth factor, beta receptor III 2.3 0.0000001
211 NM_052867 NALCN Sodium leak channel, non-selective 2.3 0.0001055
212 NM_004337 OSGIN2 Oxidative stress induced growth inhibitor family member 2 2.3 0.0000301
213 NM_000958 PTGER4 Prostaglandin E receptor 4 (subtype EP4) 2.3 0.0006466
214 NM_001033045 GPR155 G protein-coupled receptor 155 2.3 0.0000117
215 NM_032587 CARD6 Caspase recruitment domain family, member 6 2.3 0.0007864
216 NM_021197 WFDC1 WAP four-disulfide core domain 1 2.3 0.0001014
217 NM_018938 PCDHB4 Protocadherin beta 4 2.3 0.0002702
218 NM_013391 DMGDH Dimethylglycine dehydrogenase 2.3 0.0007769
219 NM_014505 KCNMB4 Potassium large conductance calcium-activated channel, subfamily M, beta member 4 2.3 0.0000254
220 NM_172366 FBXO16 F-box protein 16 2.3 0.0000801
221 NM_203403 C9orf150 Chromosome 9 open reading frame 150 2.3 0.0009304
222 NM_007048 BTN3A1 Butyrophilin, subfamily 3, member A1 2.3 0.0002037
223 NM_014737 RASSF2 Ras association (RalGDS/AF-6) domain family 2 2.3 0.0002623
224 NM_001148 ANK2 Ankyrin 2, neuronal 2.3 0.0003172
225 NM_018421 TBC1D2 TBC1 domain family, member 2 2.3 0.002261
226 NM_000824 GLRB Glycine receptor, beta 2.3 0.000148
227 NM_002121 HLA-DPB1 Major histocompatibility complex, class II, DP beta 1 2.3 0.0011187
228 NM_001289 CLIC2 Chloride intracellular channel 2 2.3 0.0000485
229 NM_020848 KIAA1462 KIAA1462 2.3 0.0000095
230 NM_004065 CDR1 Cerebellar degeneration-related protein 1, 34kDa 2.2 0.000323
231 NM_031935 HMCN1 Hemicentin 1 2.2 0.0001081
232 NM_001621 AHR Aryl hydrocarbon receptor 2.2 0.0000101
233 NM_002231 CD82 CD82 molecule 2.2 0.0000261
234 NM_018295 TMEM140 Transmembrane protein 140 2.2 0.0008474
235 NM_002970 SAT1 Spermidine/spermine N1 acetyltransferase 1 2.2 0.0000077
236 NM_001531 MR1 Major histocompatibility complex, class I-related 2.2 0.0000163
237 NM_003043 SLC6A6 Solute carrier family 6 (neurotransmitter transporter, taurine), member 6 2.2 0.0001361
238 NM_012157 FBXL2 F-box and leucine-rich repeat protein 2 2.2 0.0000359
239 NM_002309 LIF Leukemia inhibitory factor (cholinergic differentiation factor) 2.2 0.0007509
240 NM_024763 WDR78 WD repeat domain 78 2.2 0.0017849
241 NM_021945 C6orf85 Chromosome 6 open reading frame 85 2.2 0.0017489
242 NM_001218 CA12 Carbonic anhydrase XII 2.2 0.000822
243 NM_002160 TNC Tenascin C (hexabrachion) 2.2 0.0000479
244 NM_005516 HLA-E Major histocompatibility complex, class 1, E 2.2 0.0000489
245 NM_005516 HLA-E Major histocompatibility complex, class 1, E 2.2 0.0000489
246 NM_003263 TLR1 Toll-like receptor 1 2.2 0.0014844
247 NM_002117 HLA-C Major histocompatibility complex, class 1, C 2.2 0.0000444
248 NM_000247 MICA MHC class I polypeptide-related sequence A 2.2 0.0001143
249 NM_000202 IDS Iduronate 2-sulfatase (Hunter syndrome) 2.2 0.0000043
250 NM_032857 LACTB Lactamase, beta 2.2 0.0001232
251 NM_002198 IRF1 Interferon regulatory factor 1 2.2 0.0018853
252 NM_145235 FANK1 Fibronectin type III and ankyrin repeat domains 1 2.2 0.0002057
254 NM_182943 PLOD2 Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 2.2 0.0000188
255 NM_005562 LAMC2 Laminin, gamma 2 2.2 0.0012097
256 NM_144629 RFTN2 Raftlin family member 2 2.2 0.0015459
257 NM_002581 PAPPA Pregnancy-associated plasma protein A, pappalysin 1 2.2 0.000067
258 NM_004090 DUSP3 Dual specificity phosphatase 3 (vaccinia virus phosphatase VHI-related) 2.2 0.0000206
259 NM_006291 TNFAIP2 Tumor necrosis factor, alpha-induced protein 2 2.2 0.0008835
260 NM_145176 SLC2AI2 Solute carrier family 2 (facilitated glucose transporter), member 12 2.2 0.0003708
261 NM_005516 HLA-E Major histocompatibility complex, class 1, E 2.2 0.0000376
262 NM_020909 EPB41L5 Erythrocyte membrane protein band 4.1 like 5 2.2 0.0000017
263 NM_002117 HLA-C Major histocompatibility complex; class 1, C 2.2 0.0000294
264 NM_003688 CASK Calcium/calmodulin-dependent serine protein kinase (MAGUK family) 2.2 0.0000365
265 NM_001005340 GPNMB Glycoprotein (transmembrane) nmb 2.2 0.0000069
266 NM_012420 IFIT5 Interferon-induced protein with tetratricopeptide repeats 5 2.2 0.0013319
267 NM_138980 MAPK10 Mitogen-activated protein kinase 10 2.2 0.0001154
268 NM_002350 LYN V-yes-1 Yamaguchi sarcoma viral related oncogene homolog 2.2 0.0001236
269 NM_007173 PRSS23 Protease, serine, 23 2.1 0.0000224
270 ENST00000222553 PBEF1 Pre-B-cell colony enhancing factor 1 (PBEF1), mRNA 2.1 0.0006919
271 NM_014936 ENPP4 Ectonucleotide pyrophosphatase/phosphodiesterase 4 (putative function) 2.1 0.0000373
272 NM_021626 SCPEP1 Serine carboxypeptidase 1 2.1 0.0000678
273 NM_173505 ANKRD29 Ankyrin repeat domain 29 2.1 0.0000555
274 NM_000120 EPHX1 Epoxide hydrolase 1, microsomal (xenobiotic) 2.1 0.0000223
275 NM_001039580 MAP9 Microtubule-associated protein 9 2.1 0.0003664
276 NM_005746 PBEF1 Pre-B-cell colony enhancing factor 1 2.1 0.0007562
277 NM_000204 CF1 Complement factor 1 2.1 0.0015781
278 NM_021034 IFITM3 Interferon induced transmembrane protein 3 (I-8U) 2.1 0.0000542
279 NM_004734 DCLK1 Doublecortin-like kinase 1 2.1 0.0005205
280 NM_004696 SLC16A4 Solute carrier family 16, member 4 (monocarboxylic acid transporter 5) 2.1 0.0002086
281 NM_213589 RAPH1 Ras association (RalGDS/AF-6) and pleckstrin homology domains 1 2.1 0.0000129
282 NM_002395 ME1 Malic enzyme 1, NADP(+)-dependent, cytosolic 2.1 0.0000103
283 NM_014157 CCDC113 Coiled-coil domain containing 113 2.1 0.0002231
284 NR_002157 OR2A9P Olfactory receptor, family 2, subfamily A, member 9 pseudogene 2.1 0.0008517
285 NM_007112 THBS3 Thrombospondin 3 2.1 0.0000632
286 NM_005514 HLA-B Major histocompatibility complex, class 1, B 2.1 0.000079
287 NM_018933 PCDHB13 Protocadherin beta 13 2.1 0.0006096
288 NM_138452 DHRS1 Dehydrogenase/reductase (SDR family) member 1 2.1 0.0014038
289 NM_144599 NIPA1 Non imprinted in Prader-Willi/Angelman syndrome 1 2.1 0.0000307
290 XR_019525 LOC390345 Hypothetical LOC390345 2.1 0.0045174
291 NM_024642 GALNT12 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 12 (GalNAc-T12) 2.1 0.0001604
292 NM_020422 TMEM159 Transmembrane protein 159 2.1 0.0006667
293 NM_080593 HIST1H2BK Histone cluster 1, H2bk 2.1 0.0001187
294 NM_198503 KCNT2 Potassium channel, subfamily T, member 2 2.1 0.0035322
295 NM_007199 IRAK3 Interleukin-1 receptor-associated kinase 3 2.1 0.0030475
297 NM_005514 HLA-B Major histocompatibility complex, class 1, B 2 0.0002145
298 NM_003328 TXK TXK tyrosine kinase 2 0.0010901
290 NM_005419 STAT2 Signal transducer and activator of transcription 2, 113kDa 2 0.0012848
300 NM_001039706 FLJ21062 Hypothetical protein FLJ21062 2 0.001607
301 NM_015090 NFASC Neurofascin homolog (chicken) 2 0.0000349
302 NM_004159 PSMB8 Proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7) 2 0.0001761
303 NM_004159 PSMB8 Proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7) 2 0.0001761
304 NM_004159 PSMB8 Proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional peptidase 7) 2 0.0001761
305 NM_000247 MICA MHC class I polypeptide-related sequence A 2 0.0000572
306 NM_002754 MAPK13 Mitogen-activated protein kinase 13 2 0.0009883
307 NM_005929 MF12 Antigen p97 (melanoma associated) identified by monoclonal antibodies 133.2 and 96.5 2 0.0001076
308 NM_005514 HLA-B Major histocompatibility complex, class 1, B 2 0.000205
309 NM_018050 MANSC1 MANSC domain containing 1 2 0.0000755
310 NM_002121 HLA-DPB1 Major histocompatibility complex, class II, DP beta 1 2 0.000209
311 NM_018317 TBC1D19 TBC1 domain family, member 19 2 0.0000012
312 NR_003322 SNORD116-7 Small nucleolar RNA, C/D box 116-7 2 0.0051387
313 NR_003320 SNORD116-5 Small nucleolar RNA, C/D box 116-5 2 0.0051387
314 NM_020139 BDH2 3-hydroxybutyrate dehydrogenase, type 2 2 0.0000086
315 NM_004052 BNIP3 BCL2/adenovirus E1B 19kDa interacting protein 3 2 0.0001215
316 NM_021199 SQRDL Sulfide quinone reductase-like (yeast) 2 0.0008101
317 NM_153704 TMEM67 Transmembrane protein 67 2 0.0019696
318 NM_001831 CLU Clusterin 2 0.0001778
319 NM_014585 SLC40A1 Solute carrier family 40 (iron-regulated transporter), member 1 2 0.0002529
Table 5.
 
Downregulated Homozygous GCD II–Related Genes
Table 5.
 
Downregulated Homozygous GCD II–Related Genes
No. Gene Accession Gene Symbol Gene Description Change P
1 NM_181503 EXOSC8 Exosome component 8 −2.0 0.0011677
2 NM_152524 SGOL2 Shugoshin-like 2 (S. pombe) −2.0 0.0050817
3 NR_002564 SNORD26 Small nucleolar RNA, C/D box 26 −2.0 0.0002281
4 NM_003534 HIST1H3G Histone cluster 1, H3g −2.0 0.0002008
5 NM_012074 DPF3 D4, zinc and double PHD fingers, family 3 −2.0 0.0000953
6 NM_018193 FANC1 Fanconi anemia, complementation group 1 −2.0 0.0026856
7 NM_052917 GALNT13 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 13 (GalNAc-T13) −2.0 0.0008409
8 NM_152754 SEMA3D Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semapborin) 3D −2.0 0.0021798
9 NM_032117 MND1 Meiotic nuclear divisions 1 homolog (S. cerevisiae) −2.0 0.0035557
10 NM_000059 BRCA2 Breast cancer 2, early onset −2.0 0.0049817
11 NM_006079 CITED2 Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 −2.0 0.0016884
12 NM_002192 INHBA Inhibin, beta A −2.0 0.0001218
13 NM_033518 SLC38A5 Solute carrier family 38, member 5 −2.0 0.0003078
14 NM_005239 ETS2 V-ets erythroblastosis virus E26 oncogene homolog 2 (avian) −2.0 0.0000035
15 NM_001039841 ARHGAP11B Rho GTPase activating protein 11B −2.1 0.0002937
16 NM_016426 GTSE1 G-2 and S-phase expressed 1 −2.1 0.0008579
17 NM_022111 CLSPN Claspin homolog (Xenopus laevis) −2.1 0.0013778
18 NM_021968 HIST1H4J Histone cluster 1, H4j −2.1 0.0004086
19 BC067351 GUSBL1 Glucuronidase, beta-like 1 −2.1 0.0000052
20 NM_018353 C14orf106 Chromosome 14 open reading frame 106 −2.1 0.0021285
21 NM_001099293 KIF4B Kinesin family member 4B −2.1 0.0007975
22 NM_181802 UBE2C Ubiquitin-conjugating enzyme E2C −2.1 0.0016383
23 NM_014573 TMEM97 Transmembrane protein 97 −2.1 0.0004448
34 NM_182909 FILIP1L Filamin A interacting protein 1-like −2.1 0.0014915
35 NM_002823 PTMA Prothymosin, alpha (gene sequence 28) −2.1 0.0028224
36 NM_000956 PTGER2 Prostaglandin E receptor 2 (subtype EP2), 53kDa −2.1 0.0025474
37 NM_004817 TJP2 Tight junction protein 2 (zona occludens 2) −2.1 0.0000007
38 NM_007317 KIF22 Kinesin family member 22 −2.1 0.000031
39 NR_002562 SNORD28 Small nucleolar RNA, C/D box 28 −2.1 0.001433
40 NM_016095 GINS2 GINS complex subunit 2 (Psf2 homolog) −2.1 0.0018093
41 NM_007317 KIF22 Kinesin family member 22 −2.1 0.0000356
42 NM_004731 SLC16A7 Solute carrier family 16, member 7 (monocarboxylic acid transporter 2) −2.1 0.0000023
43 NM_005496 SMC4 Structural maintenance of chromosomes 4 −2.1 0.0004444
44 NM_144586 LYPD1 LY6/PLAUR domain containing 1 −2.1 0.0005818
45 NM_001129 AEBP1 AE binding protein 1 −2.1 0.0000008
46 NM_014783 ARHGAP11A Rho GTPase activating protein 11A −2.1 0.0009603
47 NM_019035 PCDH18 Protocadherin 18 −2.1 0.000004
48 NM_013277 RACGAP1 Rac GTPase activating protein 1 −2.1 0.0006113
49 NM_006739 MCM5 Minichromosome maintenance complex component 5 −2.1 0.0002303
50 NM_152270 SLFN11 Schlafen family member 11 −2.1 0.0011236
51 NM_007243 NRM Nurim (nuclear envelope membrane protein) −2.2 0.000234
52 NM_007243 NRM Nurim (nuclear envelope membrane protein) −2.2 0.000234
53 NR_003125 LOC85391 RNA, small nucleolar −2.2 0.0004524
54 NM_182751 MCM10 Minichromosome maintenance complex component 10 −2.2 0.0041059
55 NM_001048201 UHRF1 Ubiquitin-like, containing PHD and RING finger domains, 1 −2.2 0.0001459
56 NM_014465 SULT1B1 Sulfotransferase family, cytosolic, 1B, member 1 −2.2 0.0065522
57 NM_002760 PRKY Protein kinase, Y-linked −2.2 0.0047595
58 NM_001827 CKS2 CDC28 protein kinase regulatory subunit 2 −2.2 0.0009191
59 NM_004772 C5orf13 Chromosome 5 open reading frame 13 −2.2 0.0006237
60 NM_005497 GJA7 Gap junction protein, alpha 7, 45kDa −2.2 0.0001851
61 NM_001744 CAMK4 Calcium/calmodulin-dependent protein kinase IV −2.2 0.0016928
62 NM_152495 CNIH3 Cornichon homolog 3 (Drosophila) −2.2 0.0032016
63 NM_006963 ZNF22 Zinc finger protein 22 (KOX 15) −2.2 0.0005145
64 NM_014363 SACS Spastic ataxia of Charlevoix-Saguenay (sacsin) −2.2 0.0000886
65 NM_018476 BEX1 Brain expressed, X-linked 1 −2.2 0.0043276
66 NM_006727 CDH10 Cadherin 10, type 2 (T2-cadherin) −2.2 0.0003019
67 NM_003545 HIST1H4E Histone cluster 1, H4e −2.2 0.0001393
68 NM_004415 DSP Desmoplakin −2.2 0.0000256
69 NM_001761 CCNF Cyclin F −2.2 0.0000636
70 NM_018101 CDCA8 Cell division cycle associated 8 −2.3 0.0015208
71 NM_021018 HIST1H3F Histone cluster 1, H3f −2.3 0.0038466
72 NM_004572 PKP2 Plakophilin 2 −2.3 0.0008219
73 NM_003517 HIST2H2AC Histone cluster 2, H2ac −2.3 0.0003061
74 NM_022908 NT5DC2 5′-nucleotidase domain containing 2 −2.3 0.0003366
75 NM_018410 DKFZp762E1312 Hypothetical protein DKFZp762E1312 −2.3 0.0010354
76 NM_024908 WDR76 WD repeat domain 76 −2.3 0.0029464
77 NM_004456 EZH2 Enhancer of zeste homolog 2 (Drosophila) −2.3 0.000033
78 NM_198433 AURKA Aurora kinase A −2.3 0.0009593
79 NM_001878 CRABP2 Cellular retinoic acid binding protein 2 −2.3 0.0003869
80 NM_014865 NCAPD2 Non-SMC condensin 1 complex, subunit D2 −2.3 0.0000146
81 NM_006479 RAD51AP1 RAD51 associated protein 1 −2.3 0.0004349
82 NM_003541 HIST1H4K Histone cluster 1, H4k −2.3 0.0001022
83 NM_005480 TROAP Trophinin associated protein (tastin) −2.3 0.0007361
84 NM_130398 EXO1 Exonuclease 1 −2.3 0.0007009
85 NM_003530 HIST1H3D Histone cluster 1, H3d −2.3 0.0000989
86 NM_012484 HMMR Hyaluronan-mediated motility receptor (RHAMM) −2.3 0.0010368
87 BX641032 WEE1 WEE1 homolog (S. pombe) −2.3 0.0020117
88 NM_005491 CXorf6 Chromosome X open reading frame 6 −2.3 0.000069
89 NM_004900 APOBEC3B Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B −2.3 0.002503
90 NM_020890 KIAA1524 KIAA1524 −2.4 0.0035147
91 NM_012177 FBXO5 F-box protein 5 −2.4 0.0029497
92 ENST00000377738 KRTAP2-4 Keratin associated protein 2-4 (KRTAP2-4), mRNA −2.4 0.0003921
93 NM_013230 CD24 CD24 molecule −2.4 0.0032149
94 NM_001813 CENPE Centromere protein E, 312kDa −2.4 0.0019189
95 NM_007174 CIT Citron (rho-interacting, serine/threonine kinase 21) −2.4 0.0000603
96 NM_002106 H2AFZ H2A histone family, member Z −2.4 0.0010744
97 NM_003524 HIST1H2BH Histone cluster 1, H2bh −2.4 0.0001753
98 NM_003784 SERPINB7 Serpin peptidase inhibitor, clade B (ovalbumin), member 7 −2.4 0.0011738
99 NM_017669 ERCC6L Excision repair cross-complementing rodent repair deficiency, complementation group 6-like −2.4 0.0037181
100 ENST00000377738 KRTAP2-4 Keratin associated protein 2-4 (KRTAP2-4), mRNA −2.4 0.0006498
101 ENST00000377738 KRTAP2-4 Keratin associated protein 2-4 (KRTAP2-4), mRNA −2.4 0.0006498
102 NM_021052 HIST1H2AE Histone cluster 1, H2ae −2.4 0.0004919
103 NM_002263 KIFC1 Kinesin family member C1 −2.4 0.002479
104 NM_003258 TK1 Thymidine kinase 1, soluble −2.4 0.0006185
105 NM_001048198 SNHG3-RCC1 Regulator of chromosome, condensation 1 −2.4 0.0000584
106 NM_013296 GPSM2 G-protein signaling modulator 2 (AGS3-like, C. elegans) −2.4 0.0006993
107 NM_031217 KIF18A Kinesin family member 18A −2.5 0.0001562
108 NM_001017420 ESCO2 Establishment of cohesion 1 homolog 2 (S. cerevisiae) −2.5 0.0013571
109 NM_014264 PLK4 Polo-like kinase 4 (Drosophila) −2.5 0.0031529
110 ENST00000302536 KIAA1576 KIAA1576 protein (KIAA1576), mRNA −2.5 0.0000329
111 NM_031966 CCNB1 Cyclin B1 −2.5 0.0000813
112 NM_003877 SOCS2 Suppressor of cytokine signaling 2 −2.5 0.0000898
113 NM_005325 HIST1HIA Histone cluster 1, H1a −2.5 0.0000106
114 NM_138555 KIF23 Kinesin family member 23 −2.5 0.0005602
115 NM_001012507 C6orf173 Chromosome 6 open reading frame 173 −2.5 0.0003908
116 NM_002466 MYBL2 V-myb mycloblastosis viral oncogene homolog (avian)-like 2 −2.5 0.0000271
117 NM_013372 GREM1 Gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis) −2.5 0.000007
118 NM_003529 HIST1H3A Histone cluster 1, H3a −2.5 0.0012216
119 NM_001034 RRM2 Ribonucleotide reductase M2 polypeptide −2.5 0.0034171
120 NM_000599 IGFBP5 Insulin-like growth factor binding protein 5 −2.6 0.0039748
121 NM_001033049 ADARB1 Adenosine deaminase, RNA-specific, B1 (RED1 homolog rat) −2.6 0.0000097
122 NM_000561 GSTM1 Glutathione S-transferase M1 −2.6 0.0003801
123 NM_005517 HMGN2 High-mobility group nucleosomal binding domain 2 −2.6 0.0001929
124 NM_175065 HIST2H2AB Histone cluster 2, H2ab −2.6 0.0001294
125 NM_006682 FGL2 Fibrinogen-like 2 −2.6 0.0004615
126 NM_001012410 SGOL1 Shugoshin-like 1 (S. pombe) −2.6 0.0072724
127 NM_003544 HIST1H4B Histone cluster 1, H4b −2.6 0.0001657
128 NM_153262 SYT14 Synaptotagmin XIV −2.6 0.0000915
129 NM_002263 KIFC1 Kinesin family member C1 −2.7 0.0013435
130 NM_182705 FAM101B Family with sequence similarity 101, member B −2.7 0.0000477
131 NM_006558 KHDRBS3 KH domain containing, RNA binding, signal transduction associated 3 −2.7 0.0000787
132 NM_001943 DSG2 Desmoglein 2 −2.7 0.0000628
133 NM_015975 TAF9B TAF9B RNA polymerase II, TATA box binding protein (TBP)-associated factor, 31kDa −2.7 0.0001503
134 NM_016591 GCNT4 Glucosaminyl (N-acetyl) transferase 4, core 2 (beta-1,6-N-acetylglucosaminyltransferase) −2.7 0.0002032
135 NM_014875 KIF14 Kinesin family member 14 −2.7 0.0026412
136 BX641032 WEE1 WEE1 homolog (S. pombe) −2.7 0.0018471
137 NM_016588 NRN1 Neuritin 1 −2.7 0.0000023
138 NM_003546 HIST1H4L Histone cluster 1, H4l −2.7 0.0012995
139 NM_006845 KIF2C Kinesin family member 2C −2.7 0.0020828
140 NR_002612 DLEU2 Deleted in lymphocytic leukemia, 2 −2.7 0.0017015
141 NM_031299 CDCA3 Cell division cycle associated 3 −2.7 0.0002869
142 NM_018849 ABCB4 ATP-binding cassette, sub-family B (MDR/TAP), member 4 −2.8 0.000121
143 NM_001067 TOP2A Topoisomerase (DNA) II alpha 170kDa −2.8 0.0004533
144 NM_020242 KIF15 Kinesin family member 15 −2.8 0.0002493
145 NM_004439 EPHA5 EPH receptor A5 −2.8 0.0000033
146 NM_003981 PRC1 Protein regulator of cytokinesis 1 −2.8 0.0054775
147 NM_002398 MEIS1 Meis homeobox 1 −2.8 0.0003329
148 NM_173084 TRIM59 Triparite motif-containing 59 −2.8 0.001123
149 NM_003533 HIST1H31 Histone cluster 1, H3i −2.8 0.0000119
150 NM_145061 C13orf3 Chromosome 13 open reading frame 3 −2.8 0.0003047
151 NM_001786 CDC2 Cell division cycle 2, G1 to S and G2 to M −2.8 0.0035238
152 NM_006101 NDC80 NDC80 homolog, kinetochore complex component (S. cerevisiae) −2.9 0.0012085
153 NM_012112 TPX2 TPX2, microtubule-associated, homolog (Xenopus laevis) −2.9 0.0000403
154 NM_016359 NUSAP1 Nucleolar and spindle associated protein 1 −2.9 0.0011078
155 NM_003540 HIST1H4F Histone cluster 1, H4f −2.9 0.0010387
156 NM_015341 NCAPH Non-SMC condensin 1 complex, subunit H −2.9 0.0003153
157 NM_012310 KIF4A Kinesin family member 4A −2.9 0.0001634
158 NM_001211 BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) −2.9 0.0000898
159 NM_003522 HIST1H2BF Histone cluster 1, H2bf −2.9 0.0011487
160 NM_152515 CKAP2L Cytoskeleton associated protein 2-like −3.0 0.0008625
161 NM_152562 CDCA2 Cell division cycle associated 2 −3.0 0.0001478
162 NM_178229 IQGAP3 IQ motif containing GTPase activating protein 3 −3.0 0.0006081
163 NM_001884 HAPLN1 Hyaluronan and proteoglycan link protein 1 −3.0 0.0003171
164 NR_001544 CYorf14 Chromosome Y open reading frame 14 −3.0 0.0001937
165 NM_022346 NCAPG Non-SMC condensin 1 complex, subunit G −3.0 0.0016196
166 NM_002867 RAB3B RAB3B, member RAS oncogene family −3.0 0.0000771
167 NM_001080480 MBOAT1 Membrane bound O-acyltransferase domain containing 1 −3.1 0.0000156
168 NM_006350 FST Follistatin −3.1 0.0008267
169 ENST00000389239 FAM64A Family with sequence similarity 64, member A (FAM64A), mRNA −3.1 0.0003557
170 NM_020675 SPC25 SPC25, NDC80 kinetochore complex component, homolog (S. cerevisiae) −3.1 0.0024131
171 NM_170589 CASC5 Cancer susceptibility candidate 5 −3.1 0.0006033
172 NM_002497 NEK2 NIMA (never in mitosis gene a)-related kinase 2 −3.1 0.0035344
173 NM_004701 CCNB2 Cyclin B2 −3.1 0.0006401
174 NM_003318 TTK TTK protein kinase −3.1 0.0011001
175 NM_002129 HMGB2 High-mobility group box 2 −3.1 0.0003609
176 NM_018131 CEP55 Centrosomal protein 55kDa −3.1 0.0053938
177 NM_003513 HIST1H2AB Histone cluster 1, H2ab −3.1 0.000027
178 NM_001032283 TMPO Thymopoietin −3.2 0.0003481
179 NM_001255 CDC20 Cell division cycle 20 homolog (S. cerevisiae) −3.2 0.0000258
180 NM_001711 BGN Biglycan −3.2 0.0000375
181 NM_001071 TYMS Thymidylate synthetase −3.2 0.0032506
182 NM_004934 CDH18 Cadherin 18, type 2 −3.2 0.0000862
183 NM_018136 ASPM Asp (abnormal spindle) homolog, microcephaly associated (Drosophila) −3.2 0.0001314
184 NM_020859 SHROOM3 Shroom family member 3 −3.2 0.0002947
185 NM_006147 IRF6 Interferon regulatory factor 6 −3.2 0.0002558
186 NM_018685 ANLN Anillin, actin binding protein −3.2 0.0004383
187 NM_005321 HIST1H1E Histone cluster 1, H1e −3.3 0.0000589
188 NM_017779 DEPDC1 DEP domain containing 1 −3.3 0.0005434
189 NM_002783 PSG7 Pregnancy specific beta-1-glycoprotein 7 −3.3 0.0002987
190 NM_005556 KRT7 Keratin 7 −3.4 0.0000318
191 NM_005322 HIST1H1B Histone cluster 1, H1b −3.4 0.000073
192 NM_014736 KIAA0101 KIAA0101 −3.4 0.0073048
193 NM_202002 FOXM1 Forkhead box M1 −3.4 0.0009265
194 NM_005030 PLK1 Polo-like kinase 1 (Drosophila) −3.4 0.0000316
195 NM_006461 SPAG5 Sperm associated antigen 5 −3.4 0.0002157
196 NM_016343 CENPF Centromere protein F, 350/400ka (mitosin) −3.5 0.0053205
197 NM_000609 CXCL12 Chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1) −3.5 0.0000196
198 NM_018689 KIAA1199 KIAA1199 −3.6 0.0000461
199 NM_145697 NUF2 NUF2, NDC80 kinetochore complex component, homolog (S. cerevisiae) −3.6 0.0008586
200 NM_005573 LMNB1 Lamin B1 −3.7 0.0000014
201 NM_203401 STMN1 Stathmin 1/oncoprotein 18 −3.8 0.0000397
202 NM_006013 RPL10 Ribosomal protein L10 −3.8 0.0000282
203 NM_014750 DLG7 Discs, large homolog 7 (Drosophila) −3.9 0.0004194
204 NM_003638 ITGA8 Integrin, alpha 8 −4.0 0.0005969
205 NM_003537 HIST1H3B Histone cluster 1, H3b −4.0 0.0033207
206 NM_014932 NLGN1 Neuroligin 1 −4.2 0.0048918
207 NR_003106 PWCR1 Prader-Willi syndrome chromosome region 1 −4.2 0.0041387
208 NM_002276 KRT19 Keratin 19 −4.2 0.0002805
209 NM_005733 KIF20A Kinesin family member 20A −4.3 0.005152
210 NM_001290 LDB2 LIM domain binding 2 −4.4 0.0000202
211 NM_001080428 ODZ2 Odz, odd Oz/ten-m homolog 2 (Drosophila) −4.5 0.0001199
212 NM_003521 HIST1H2BM Histone cluster 1, H2bm −4.5 0.0000106
213 NM_018284 GBP3 Guanylate binding protein 3 −4.6 0.0002522
214 NM_013381 TRHDE Thyrotropin-releasing hormone degrading enzyme −4.7 0.0001288
215 NM_001040152 PEG10 Paternally expressed 10 −4.7 0.0000323
216 NM_005159 ACTC1 Actin, alpha, cardiac muscle 1 −4.7 0.0000545
217 NM_003542 HIST1H4C Histone cluster 1, H4c −5.2 0.0002514
218 NM_022350 LRAP Leukocyte-derived arginine aminopeptidase −5.2 0.0000817
219 NM_002421 MMP1 Matrix metallopeptidase 1 (interstitial collagenase) −5.5 0.0047864
220 NM_002781 PSG5 Pregnancy specific beta-1-glycoprotein 5 −5.6 0.0000083
221 NM_005711 EDIL3 EGF-like repeats and discoidin 1-like domains 3 −6.5 0.0000014
222 NM_003411 ZFY Zinc finger protein, Y-linked −6.5 0.0000338
223 NM_005434 MALL Mal, T-cell differentiation protein-like −7.5 0.0000132
224 NM_004653 JARID1D Jumonji, AT rich interactive domain 1D −9.0 0.0000055
225 NM_001005852 CYorf15A Chromosome Y open reading frame 15A −9.7 0.0000309
226 NM_004932 CDH6 Cadherin 6, type 2, K-cadherin (fetal kidney) −10.2 0.0000005
227 NM_032576 CYorf15B Chromosome Y open reading frame 15B −11.1 0.0000012
228 NM_007125 UTY Ubiquitously transcribed tetratricopeptide repeat gene, Y-linked −11.2 0.0000027
229 NM_014893 NLGN4Y Neuroligin 4, Y-linked −11.8 0.0001143
230 NM_021013 KRT34 Keratin 34 −12.1 0.0000017
231 NM_004654 USP9Y Ubiquitin specific peptidase 9, Y-linked (fat facets-like, Drosophila) −16.3 0.0000009
232 NM_005045 RELN Reelin −17.4 0.0001692
233 NM_004681 EIF1AY Eukaryotic translation initiation factor 1A, Y-linked −19.5 0.0014353
234 NM_001008 RPS4Y1 Ribosomal protein S4, Y-linked 1 −27.2 0.0000016
235 NM_001999 FBN2 Fibrillin 2 (congenital contractural arachnodactyly) −47.8 0.0000903
236 NM_004660 DDX3Y DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked −59.9 0.0002855
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