November 2007
Volume 48, Issue 11
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Cornea  |   November 2007
Mutations in the UBIAD1 Gene on Chromosome Short Arm 1, Region 36, Cause Schnyder Crystalline Corneal Dystrophy
Author Affiliations
  • Jayne S. Weiss
    From the Kresge Eye Institute, the
    Departments of Ophthalmology and
  • Howard S. Kruth
    Section of Experimental Atherosclerosis, National Institutes of Health, Bethesda, Maryland;
  • Helena Kuivaniemi
    Surgery, and the
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan; the
  • Gerard Tromp
    Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan; the
  • Peter S. White
    Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; the
  • R. Scott Winters
    Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; the
  • Walter Lisch
    Department of Ophthalmology, Klinikum Hanau, Hanau, Germany; the
  • Wolfram Henn
    Departments of Human Genetics and
  • Elke Denninger
    Ophthalmology, Saarland University, Homburg-Saar, Germany; the
  • Matthias Krause
    Ophthalmology, Saarland University, Homburg-Saar, Germany; the
  • Paul Wasson
    Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; the
  • Neil Ebenezer
    Department of Molecular Genetics, The Institute of Ophthalmology, University College London, London, United Kingdom; and
  • Sunil Mahurkar
    Transgenomic, Gaithersburg, Maryland.
  • Michael L. Nickerson
    Transgenomic, Gaithersburg, Maryland.
Investigative Ophthalmology & Visual Science November 2007, Vol.48, 5007-5012. doi:10.1167/iovs.07-0845
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      Jayne S. Weiss, Howard S. Kruth, Helena Kuivaniemi, Gerard Tromp, Peter S. White, R. Scott Winters, Walter Lisch, Wolfram Henn, Elke Denninger, Matthias Krause, Paul Wasson, Neil Ebenezer, Sunil Mahurkar, Michael L. Nickerson; Mutations in the UBIAD1 Gene on Chromosome Short Arm 1, Region 36, Cause Schnyder Crystalline Corneal Dystrophy. Invest. Ophthalmol. Vis. Sci. 2007;48(11):5007-5012. doi: 10.1167/iovs.07-0845.

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      © 2015 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. Schnyder crystalline corneal dystrophy (SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed.

methods. DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5′ untranslated region (UTR) exons.

results. No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples (200 chromosomes).

conclusions. Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains.

Schnyder crystalline corneal dystrophy (SCCD: OMIM 121800; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD) was initially described by Van Went and Wibaut in the Dutch literature in 1924, when they reported the characteristic corneal changes in a three-generation family. 1 Subsequently, in 1929, the Swiss ophthalmologist Walter Schnyder, published a report of the same disease in a different three-generation family. 2 3 The autosomal dominant disease became known as Schnyder crystalline corneal dystrophy, and is characterized by the abnormal deposition of cholesterol and phospholipids in the cornea. 4 The resultant progressive bilateral corneal opacification leads to decreasing visual acuity. 
SCCD is considered to be a rare dystrophy, with fewer than 150 articles in the published literature, and most articles reporting only a few affected persons. In the late 1980s, we identified four large Swede-Finn pedigrees of patients with SCCD in central Massachusetts and published the results of clinical examinations of 33 affected individuals. 5 6 In two of the original Swede-Finn pedigrees, a genome-wide DNA linkage analysis mapped the SCCD locus within a 16-cM interval between markers D1S2633 and D1S228 on chromosome short arm 1, region 36. 7 In a subsequent study, 13 pedigrees were used to perform haplotype analysis by using densely spaced microsatellite markers refining the candidate interval to 2.32 Mbp between markers D1S1160 and D1S1635. A founder effect was implied by the common disease haplotype that was present in the initial Swede-Finn pedigrees. Identity by state was present in all 13 families for two markers, D1S244 and D1S3153, further narrowing the candidate region to 1.57 Mbp. 8 9  
We (unpublished results, 2005) and others 10 performed a candidate gene analysis for mutations by sequencing the exonic regions of ENO1, CA6, LOC127324, SLC2A5, SLC25A33, PIK3CD, CLSTN1, CTNNBIP1, LZIC, NMNAT, RBP7, UBE4B, K1F1B, PGD, CORT, DFFA, and PEX14. No pathogenic mutations were found. In May 2007, Oleynikov et al. (IOVS 2007;48:ARVO E-Abstract 549) reported results of mutation screening of the remaining 16 of the 31 genes that were within the 2.32-Mbp candidate region for SCCD on the short arm of chromosome 1. They found no disease-causing mutations in the patients with SCCD. Possible explanations for the absence of mutations in any of the 31 genes studied included locus heterogeneity for SCCD, incomplete gene annotation for the candidate interval, the presence of pathogenic mutations outside the coding regions of candidate genes, or an error in the assignment of the candidate locus for SCCD due to misclassification of disease status in family members. Indeed, reanalysis of the pedigrees reported in an article by Theendakara et al. 9 showed a misclassification in one individual. Individual III-5 in family 9 was reported by herself and her father not to have SCCD. Rereview of the patient’s clinical chart, however, revealed that she had evidence of subtle SCCD without crystals. The phenotype in the patient’s family was atypical, with some affected members having had only a diffuse, confluent corneal clouding without crystal deposition. 11 In a recent article 11 detailing the phenotypic variations and long-term visual morbidity in 33 pedigrees with SCCD, family 9 was identified as family J. When compared with the corneal findings in other SCCD families, the dystrophy phenotype in family 9 appeared to be mild, resulting in less visual morbidity than in other SCCD pedigrees. Affected members of family 9 often maintained excellent visual acuity well into old age. Family 9 had been used to define the centromeric boundary of the candidate interval at D1S1635. 9 We decided to remove family 9 from the analysis and re-evaluate the haplotypes in only the other 12 families. This resulted in a shift of the centromeric boundary of the candidate interval from D1S1635 to D1S2667. The expanded candidate interval included C1orf127, TARDBP, MASP2, SRM, EXOSC10, FRAP1, ANGPTL7, UBIAD1, and LOC39906. We chose three genes: ANGPTL7 (NCBI Entrez Gene ID: 10218; http://www.ncbi.nlm.nih.gov/gene; provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD), FRAP1 (NCBI Entrez Gene ID: 2475), and UB1AD1 (NCBI Entrez Gene ID: 29914); for initial examination. ANGPTL7 and UBIAD1 were included in the study, because both were expressed in the cornea. FRAP1 and UBIAD1 were included because of their known involvement in lipid metabolism, diabetes, and nutrient signaling. 12 13 14 15 16  
Methods
Sample Collection
The recruitment efforts which spanned from 1987 to the present have been described in prior publications 7 9 with Institutional Review Board approval of the study obtained from University of Massachusetts Medical Center from 1992 to 1995 and subsequently from Wayne State University to the present. Written informed consent was obtained from all adult participants and the parents of minor participants according to the research tenets of the Declaration of Helsinki. Ophthalmic examination included assessment of visual acuity and performance of slit lamp examination to assess corneal findings. Blood samples were collected from individuals from six unrelated SCCD pedigrees. Three of these pedigrees had DNA samples available on at least four individuals (Figs. 1 2 3) . Genotyping of two of these families, Q and Y, has been reported. They were identified as pedigrees 11 and 12, respectively, in the article by Theendakara et al. 9 Genotyping of family T has not been reported. DNA from two individuals in family U, one affected and one unaffected as well as a single affected member from two additional families were also examined. The six families with SCCD were Caucasian, with one family from Germany, two families from England, and three American families, one of mixed European ancestry and the others of unknown ancestry. An independent set of 100 commercially available normal Caucasian DNA samples from individuals of European ancestry (Coriell Cell Repositories, Camden, NJ) was examined for each mutation, to ensure that mutations were novel, associated with SCCD disease, and were not rare single nucleotide polymorphisms (SNPs). 
DNA Isolation and PCR
Genomic DNA was isolated using a DNA isolation kit (Puregene; GentraSystems, Minneapolis, MN). DNA samples were quantified by spectrophotometer (ND-1000; NanoDrop; Wilmington, DE) and then diluted to an approximately 20-ng/μL working solution. 
PCR products were designed to amplify exons and RNA splice junctions. Amplification of DNA was performed in 25-μL reactions with 50 ng of genomic DNA and Taq DNA polymerase (Hot-Start; Denville Scientific, Metuchen, NJ) with 1× reaction buffer, 0.2 mM of each dNTP, and 0.2 μM each of forward and reverse primers. Thermal cycling was accomplished on commercial systems (Dyad and Tetrad DNA Engines; MJ Research-Bio-Rad; Waltham, MA) with a program of 95°C for 2 minutes, 10 cycles of touchdown PCR, and then 30 cycles of 95°C for 30 seconds, 58°C for 30 seconds, and 68°C for 30 seconds, followed by a final 5-minute extension at 68°C. PCR products (5 μL) were analyzed on 2% agarose gels and visualized with ethidium bromide. 
DNA Sequencing
In some cases, before sequencing, excess PCR primers were removed from 10 μL of PCR product (Ampure PCR Purification; Agencourt Bioscience, Beverly, MA). The purified product was eluted in 30 μL of deionized water. Reaction chemistry (BigDye v. 3.1; Applied Biosystems, Inc. [ABI] Foster City, CA) and cycle sequencing were adapted from the manufacturer’s recommendations. Cycle-sequencing products were purified (CleanSeq reagents; Agencourt Bioscience Corp.), eluted in 40 μL of 0.01 μM EDTA, and 30 μL was run on a DNA sequencer (model 3100; ABI). Sequence chromatograms were analyzed on computer (Sequencher software; GeneCodes, Ann Arbor, MI) to visualize and align sequence chromatograms. The UCSC genome browser (www.genome.ucsc.edu/ provided in the public domain by the Genome Bioinformatics Group of the University of California, Santa Cruz) and Mutation Discovery (www.mutationdiscovery.com) were used for protein and single-nucleotide polymorphism (SNP) annotation. 
Results
All protein coding regions, splice junctions, and 5′ untranslated region (UTR) exons were examined in the FRAP1, ANGPTL7, and UBIAD1 genes. Sequence variants were found in the FRAP1 and ANGPTL7 genes, but they were either present in both affected and unaffected individuals or were annotated in the SNP database (dbSNP, data not shown), In UBIAD1, DNA sequencing revealed mutations in affected members of all six families examined (Table 1 , Fig. 4 ). In family Q (Fig. 1) , two affected and two unaffected individuals were sequenced, and both of the affected members (II-10 and III-11) shared the N102S mutation, whereas the unaffected ones (I-1 and II-9) did not have this mutation. Both affected persons showed evidence of corneal crystal deposition on slit lamp examination. The clinical status of III-12, a 19-year-old female who had been classified as unaffected in an earlier study, 9 was not clear. The examiner was unsure whether this patient might have a slight corneal haze suggestive of early SCCD without crystals. Sequencing revealed that she had an allele with the N102S mutation in two independent DNA samples, reducing the likelihood of sample mislabeling or other technical errors. It was noted that the disease haplotype was shared by all three affected individuals after haplotype reconstruction, using the corrected clinical classification. 9  
Family T (Fig. 2)was found to have a G177R mutation in both affected siblings (III-2 and III-3) available for the study and in neither of the two unaffected children (IV-1 and IV-2) of individual III-2. An unaffected spouse (III-4) also did not have the mutation. The third SCCD family, family Y (Fig. 3) , had the same mutation as family Q in all five affected members available for the study. The one unaffected sibling (III-6) and her unaffected mother (II-4), whose DNA was also sequenced, did not have the mutation. 
The N102S mutation was also found in three other unrelated, small SCCD families. An affected individual from family U possessed the N102S mutation, whereas the unaffected sibling did not. Finally, the N102S mutation was found in two additional families (BB1 and BB2), each one with one affected individual available for the study. The ethnicity of the five unrelated pedigrees with the N102S mutation varied. Family Y was from Germany, families Q and U were from the United States, and families BB1 and BB2 were from England. 
In summary, all the 12 definitively affected individuals analyzed in the six families had alterations that were not found in any of the 7 unaffected blood relatives. The only exception was one individual who had a mutation, but whose clinical phenotype was indecisive. Each mutation therefore cosegregated with the disease and was not seen in any of those family members who were definitively diagnosed on slit lamp examination as unaffected. Furthermore, the UBIAD1 gene was examined in 100 Caucasian control DNAs from normal individuals of European ancestry, and neither alteration was observed. 
Both mutations changed highly conserved bases and led to substitutions of amino acids conserved in 11 of 12 vertebrate species ranging from telostomes to human. The only species that diverged at N102S was the platypus, which had an isoleucine at amino acid 102, and the armadillo, which had two amino acids deleted at G177R. This evolutionary conservation potentially indicates key roles for these amino acids in normal function of the protein. The UBIAD1 locus produces five transcripts that share exon 1, but exons 2 through 5 are transcript specific. Also, transcripts A, C, D, and F, share exons 1 and 2, which comprise the curated UBIAD1 transcript (RefSeq NM_013319; Fig. 4 ). The predicted protein structure for transcript A is shown in Figure 5
Discussion
Difficulty of Making the Diagnosis
Despite the name, Schnyder crystalline corneal dystrophy, only 50% of affected patients have been reported to demonstrate corneal crystals. 5 6 11 Nevertheless, the pattern of progressive corneal opacification is predictable based on age, regardless of the presence or absence of crystalline deposition. 5 Although SCCD with crystals may be diagnosed as early as 17 months of age, diagnosis of SCCD without crystals may be delayed to the fourth decade, because it is difficult to determine when the cornea demonstrates the first changes of subtle panstromal haze. 5 6 11 Consequently, the assignment of an unaffected phenotype is more challenging in younger patients and may explain the findings in the 19-year-old female patient (III-12 in pedigree Q) who had been classified as clinically unaffected. 9 This patient possessed the disease haplotype and the mutation (N102S), which was also found in her affected brother, father (Fig. 6) , and two paternal aunts. The alternative explanation is incomplete penetrance, a common phenomenon. 
Corneal Lipid Deposition in SCCD
Corneal arcus has been found to develop in patients with SCCD by 23 years of age. 5 While premature occurrence of corneal arcus is reported to be associated with coronary artery disease 17 18 19 it may occur independent of abnormal lipid levels or other systemic disorders. 20 Hypercholesterolemia is present in up to two thirds of patients with SCCD.40 21 22 Although familial hypertriglyceridemia and dysbetalipoproteinemia have been reported, familial hypercholesterolemia is the most common lipoprotein abnormality 23 in patients with SCCD. These abnormalities may also occur in members of the SCCD pedigrees who are reported to be unaffected by the corneal dystrophy. 20 24 25 26 By comparison, the Cavalier King Charles Spaniel and Rough Collie breeds of dog with crystalline dystrophy usually have normal serum lipid levels. 27  
Previously, the systemic hyperlipidemia in SCCD was postulated to be the primary defect that results in corneal clouding, 28 but this theory lost favor when others documented that patients affected with SCCD may have either normal or abnormal serum lipid, lipoprotein, or cholesterol levels and that the progress of the corneal opacification is not related to the serum lipid levels. 29 30 Lisch followed 13 patients with SCCD for 9 years and concluded that no link could be drawn between the corneal findings and systemic hyperlipidemia, although 8 of 12 patients had elevated cholesterol or apolipoprotein B levels and 6 of 8 had dyslipoproteinemia type IIa. 29  
It has been proposed that the mutated gene responsible for SCCD results in an imbalance in local factors affecting lipid/cholesterol transport or metabolism. A temperature-dependent enzyme defect has been postulated because the initial cholesterol deposition occurs in the axial/paraxial cornea, which is the coolest part of the cornea. 23 31 Burns et al. 31 documented the cornea as an active uptake and storage site for cholesterol. They injected radiolabeled 14C-cholesterol 11 days before removing a patient’s cornea during penetrating keratoplasty (PKP) and demonstrated that the level of radiolabeled cholesterol was higher in the cornea than in the serum at the time of surgery. 31 Furthermore, lipid analysis of the corneal specimens from patients affected with SCCD who have undergone PKP revealed that the apolipoprotein constituents of HDL (apo A-I, A-II, and E) were accumulated in the central cornea, whereas those of LDL (apo B) were absent. This suggests an abnormality confined to HDL metabolism. 32  
Because of its smaller size, HDL would be the only lipoprotein that could freely diffuse, while intact, to the central cornea. The size of the larger lipoproteins would prevent their free diffusion unless they were modified. 33 HDL concentrations are inversely related to the incidence of coronary atherosclerosis. 34 Consequently, SCCD lipid accumulation could be caused by a local defect of HDL metabolism. Alternatively, because HDL-related apolipoproteins tend to associate with lipid, the accumulation of these apolipoproteins in the cornea could be secondary to lipid that accumulates in the cornea for some other reason. 
The notion that the gene for SCCD plays an important role in lipid–lipoprotein metabolism throughout the body is supported in a report by Battisti et al., 35 who cultured the skin fibroblasts of a patient with SCCD. Although membrane-bound spherical vacuoles with lipid materials suggesting storage lipids were present in the skin, there are no other reports in the literature that their experiments have been repeated. 
UBIAD1 and Lipid Metabolism
UBIAD1 (UbiA prenyltransferase domain containing 1) was of interest to us, as this gene produces a protein that is predicted to contain several transmembrane helices and a prenyltransferase domain that could play a role in cholesterol metabolism. UBIAD1 was previously known as TERE1 (transitional epithelia response protein 1 or RP4-796F18) and the transcript is present in most normal human tissues, including the cornea. 13 Although there is significant evidence that the RefSeq transcript (2 exons) is in the cornea, evidence of specific expression of the longer transcripts in the cornea is inconclusive. Expressed sequence tags have been isolated from the cornea but information about specific localization of the protein within the cornea is not known. McGarvey et al. 14 demonstrated that the expression of this gene is greatly decreased in prostate carcinoma. UBIAD1 interacts with the C-terminal portion of apo E, 14 15 which is known to be important in reverse cholesterol transport, because it helps mediate cholesterol solubilization and removal from cells. 36 37 Apolipoprotein E has been found to be present at increased levels in corneal specimens from SCCD corneas. 32 Consequently, a potential mechanism for UBIAD1–mediated cornea lipid cholesterol accumulation in the cornea is that altered interaction with apo E, and possibly other HDL lipid solubilizing apolipoproteins, results in decreased cholesterol removal from the cornea. 
There is another possible mechanism by which a mutation in the UBIAD1 gene could cause corneal cholesterol accumulation. This gene contains a prenyl-transferase domain, suggesting that the gene may function in cholesterol synthesis. Prenylation reactions are involved in cholesterol synthesis and the synthesis of geranylgeraniol, an inhibitor of HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis. 38 Thus, it is possible that UBIAD1 functions in regulating cholesterol synthesis and that excess cholesterol synthesis occurs when this gene is defective. In this regard, increased cholesterol synthesis in the liver and other tissues would be expected to downregulate the LDL receptor that mediates removal of LDL from the blood, thus accounting for the elevated LDL blood levels often observed in patients with SCCD. 
The potential consequences of the mutations described in this study on UBIAD1 protein function should be investigated. The occurrence of the N102S mutation in five unrelated SCCD families of different ethnicity suggests that this may be a mutation hot spot. The location of these alterations relative to the structure of the protein in the membrane is also interesting. Both occur at sites in the protein where transmembrane helices exit the membrane and thus are located at the hydrophic–hydrophilic interface. Altered organization of the protein in the membrane may affect prenyl-transferase activity or alter interactions with substrates of binding partners. The UBIAD1 locus produces five transcripts that share exon 1, but exons 2 through 5 are transcript specific. An expanded mutation spectrum may help identify which transcript produces the protein that, when mutated, causes SCCD. Furthermore, an expanded spectrum of mutations may assist in identification of genotype–phenotype correlations that highlight specific functions of the protein that, when mutated, lead to family-specific SCCD characteristics. Since submission of the present study, Orr et al. 39 have published independent results with mutations in the UBIAD1 gene in five unrelated families. Of interest, one of the families had the N102S mutation that was present in five of our families. 
 
Figure 1.
 
Family Q from the United States. (*) Individuals whose DNA was used for DNA sequencing. Individual III-12, a 19-year-old woman, did not have corneal crystal deposition on clinical examination but had trace haziness of the cornea. It was not clear whether she had the disease phenotype because of the minimal corneal changes but genotyping demonstrated that this individual carried the disease haplotype. 9
Figure 1.
 
Family Q from the United States. (*) Individuals whose DNA was used for DNA sequencing. Individual III-12, a 19-year-old woman, did not have corneal crystal deposition on clinical examination but had trace haziness of the cornea. It was not clear whether she had the disease phenotype because of the minimal corneal changes but genotyping demonstrated that this individual carried the disease haplotype. 9
Figure 2.
 
Family T from the United States. (*) Individuals whose DNA was used for DNA sequencing.
Figure 2.
 
Family T from the United States. (*) Individuals whose DNA was used for DNA sequencing.
Figure 3.
 
Family Y from Germany. (*) Individuals whose DNA was used for DNA sequencing.
Figure 3.
 
Family Y from Germany. (*) Individuals whose DNA was used for DNA sequencing.
Table 1.
 
Mutations Identified in Six SCCD Families
Table 1.
 
Mutations Identified in Six SCCD Families
Family and Individual ID Mutation Codon
T III-3 GGT>CGT G177R
Q II-11 AAC>AGC N102S
Y II-3 AAC>AGC N102S
U AAC>AGC N102S
BB1 AAC>AGC N102S
BB2 AAC>AGC N102S
Figure 4.
 
Summary of transcripts in UBIAD1 locus (Gene ID: 29914). (A) RefSeq curated transcript representing the best available data (RefSeq NM_013319); (B-F) transcripts that are possible based on alignment of spliced ESTs. Transcript E may represent alternative promoter usage, rather than alternative splicing. Mutations were found in exon 1 of transcript A. Exons are numbered 1 to 5 beginning at transcription start site.
Figure 4.
 
Summary of transcripts in UBIAD1 locus (Gene ID: 29914). (A) RefSeq curated transcript representing the best available data (RefSeq NM_013319); (B-F) transcripts that are possible based on alignment of spliced ESTs. Transcript E may represent alternative promoter usage, rather than alternative splicing. Mutations were found in exon 1 of transcript A. Exons are numbered 1 to 5 beginning at transcription start site.
Figure 5.
 
Transcript A (see Fig. 4 ; RefSeq NM_013319) encodes a protein of 338 amino acids. Transmembrane-spanning regions (dark gray), labeled 1 through 8, are shown in their approximate locations and correspond to amino acids 83-103, 134-154, 160-180, 188-208, 209-229, 245-267, 277-297, and 315-335. The prenyl-transferase domain us indicated by the horizontal line at top and comprises amino acids 58-333 the top. Locations of the two SCCD mutations identified in this study are indicated below the protein (arrows).
Figure 5.
 
Transcript A (see Fig. 4 ; RefSeq NM_013319) encodes a protein of 338 amino acids. Transmembrane-spanning regions (dark gray), labeled 1 through 8, are shown in their approximate locations and correspond to amino acids 83-103, 134-154, 160-180, 188-208, 209-229, 245-267, 277-297, and 315-335. The prenyl-transferase domain us indicated by the horizontal line at top and comprises amino acids 58-333 the top. Locations of the two SCCD mutations identified in this study are indicated below the protein (arrows).
Figure 6.
 
A patient with crystals in the central corneal. Individual II-10 in family Q is a 43-year-old man with central corneal crystals, mid-peripheral haze and arcus lipoides. Best corrected visual acuity was 20/50.
Figure 6.
 
A patient with crystals in the central corneal. Individual II-10 in family Q is a 43-year-old man with central corneal crystals, mid-peripheral haze and arcus lipoides. Best corrected visual acuity was 20/50.
The authors thank Chaesik Kim, Karen Volz, Beth Silvis, Jennifer Cox, Stephen R. Powell, Heath Lemley, Alana Weiss Nydorf, and Yaoying Wang for valuable contributions to the study. 
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Figure 1.
 
Family Q from the United States. (*) Individuals whose DNA was used for DNA sequencing. Individual III-12, a 19-year-old woman, did not have corneal crystal deposition on clinical examination but had trace haziness of the cornea. It was not clear whether she had the disease phenotype because of the minimal corneal changes but genotyping demonstrated that this individual carried the disease haplotype. 9
Figure 1.
 
Family Q from the United States. (*) Individuals whose DNA was used for DNA sequencing. Individual III-12, a 19-year-old woman, did not have corneal crystal deposition on clinical examination but had trace haziness of the cornea. It was not clear whether she had the disease phenotype because of the minimal corneal changes but genotyping demonstrated that this individual carried the disease haplotype. 9
Figure 2.
 
Family T from the United States. (*) Individuals whose DNA was used for DNA sequencing.
Figure 2.
 
Family T from the United States. (*) Individuals whose DNA was used for DNA sequencing.
Figure 3.
 
Family Y from Germany. (*) Individuals whose DNA was used for DNA sequencing.
Figure 3.
 
Family Y from Germany. (*) Individuals whose DNA was used for DNA sequencing.
Figure 4.
 
Summary of transcripts in UBIAD1 locus (Gene ID: 29914). (A) RefSeq curated transcript representing the best available data (RefSeq NM_013319); (B-F) transcripts that are possible based on alignment of spliced ESTs. Transcript E may represent alternative promoter usage, rather than alternative splicing. Mutations were found in exon 1 of transcript A. Exons are numbered 1 to 5 beginning at transcription start site.
Figure 4.
 
Summary of transcripts in UBIAD1 locus (Gene ID: 29914). (A) RefSeq curated transcript representing the best available data (RefSeq NM_013319); (B-F) transcripts that are possible based on alignment of spliced ESTs. Transcript E may represent alternative promoter usage, rather than alternative splicing. Mutations were found in exon 1 of transcript A. Exons are numbered 1 to 5 beginning at transcription start site.
Figure 5.
 
Transcript A (see Fig. 4 ; RefSeq NM_013319) encodes a protein of 338 amino acids. Transmembrane-spanning regions (dark gray), labeled 1 through 8, are shown in their approximate locations and correspond to amino acids 83-103, 134-154, 160-180, 188-208, 209-229, 245-267, 277-297, and 315-335. The prenyl-transferase domain us indicated by the horizontal line at top and comprises amino acids 58-333 the top. Locations of the two SCCD mutations identified in this study are indicated below the protein (arrows).
Figure 5.
 
Transcript A (see Fig. 4 ; RefSeq NM_013319) encodes a protein of 338 amino acids. Transmembrane-spanning regions (dark gray), labeled 1 through 8, are shown in their approximate locations and correspond to amino acids 83-103, 134-154, 160-180, 188-208, 209-229, 245-267, 277-297, and 315-335. The prenyl-transferase domain us indicated by the horizontal line at top and comprises amino acids 58-333 the top. Locations of the two SCCD mutations identified in this study are indicated below the protein (arrows).
Figure 6.
 
A patient with crystals in the central corneal. Individual II-10 in family Q is a 43-year-old man with central corneal crystals, mid-peripheral haze and arcus lipoides. Best corrected visual acuity was 20/50.
Figure 6.
 
A patient with crystals in the central corneal. Individual II-10 in family Q is a 43-year-old man with central corneal crystals, mid-peripheral haze and arcus lipoides. Best corrected visual acuity was 20/50.
Table 1.
 
Mutations Identified in Six SCCD Families
Table 1.
 
Mutations Identified in Six SCCD Families
Family and Individual ID Mutation Codon
T III-3 GGT>CGT G177R
Q II-11 AAC>AGC N102S
Y II-3 AAC>AGC N102S
U AAC>AGC N102S
BB1 AAC>AGC N102S
BB2 AAC>AGC N102S
Copyright 2007 The Association for Research in Vision and Ophthalmology, Inc.
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