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Colby C. Uptegraft, Pimkwan Jaru-ampornpan, Jessica Wenzler, Tina Iverson, John Kuchtey, Rachel W. Kuchtey; Screening Open-angle Glaucoma Patients For Mutations In The Candidate Glaucoma Gene ADAMTS10. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2414.
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We recently identified ADAMTS10 as a candidate glaucoma gene in the Beagle model of inherited primary open-angle glaucoma (POAG). The purpose of this study is to investigate the association of ADAMTS10 (GenBank/NG_011840) with human glaucoma.
Patients with open-angle glaucoma were identified for a pilot screening of the exon and exon/intron junction regions of ADAMTS10 by Sanger sequencing. These patients include 12 primary congenital glaucoma (PCG), 16 juvenile open-angle glaucoma (JOAG), 3 adult-onset POAG, 15 pseudoexfoliation glaucoma (PEXG) and 18 pigment-dispersion glaucoma (PDG) patients. Nineteen cataract control patients (CC) without glaucoma were also included in the pilot cohort. Primers were designed using Primer3 v. 0. 4. 0. The JOAG patients were first screened for mutations in MYOC (GenBank/NG_008859) while the PCG patients were first screened for CYP1B1 (GenBank/NG_008386) mutations. Sequencing results were analyzed with Sequencher 4.9. Novel non-synonymous (NS) variants were confirmed with either restriction digests and/or resequencing. I-TASSER was used for structural homology modeling.
Sequencing revealed 21 SNPs in ADAMTS10, 8 of which have been reported in dbSNP. Five of the 8 reported SNPs were found in both glaucoma patients and CC patients. These 5 SNPs represent the only SNPs found in CC patients making the other 16/21 unique to glaucoma patients. Among these 16 SNPs, 3 were novel, including 2 NS, and 1 located in an intron within 6bp of an int/ex junction. One novel NS SNP in exon 17 resulting in A655V was found in a JOAG patient of Ethiopian decent. This human variant is located 7 AA proximal to the AA change associated with POAG in beagles. Protein modeling revealed that this change located in a cysteine-rich domain likely decreases the affinity for a binding partner by perturbing the side chain of F616.
Sequencing ADAMTS10 in patients with various types of open-angle glaucoma revealed 2 novel NS SNPs and 1 novel int/ex junction SNP not present in control patients. These 3 variants are potential candidates for glaucoma-associated mutations in ADAMTS10 in human glaucoma. Further screening of 79 additional adult-onset POAG patients is underway.
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