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Colin Marrs, Sarah Garnai, Namita Natalie Lopes, David Reed, Kari Branham, Mohammad Othman, Sayoko Moroi, John Heckenlively, Hemant Pawar, Julia Richards; Spatial Distribution of Mutations in ASB10 and MYOC. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6244.
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To evaluate distribution of specific mutation types in ASB10 and MYOC, two genes that have been implicated in open-angle glaucoma (OAG).
All subjects provided informed consent under a protocol approved by the University of Michigan Institutional Review Board. The inclusion criteria met standards used in the NEIGHBOR genome-wide association study. Features of OAG cases included age at onset ≥35 years, either high or normal intraocular pressures (IOP), glaucomatous optic disc cupping, glaucomatous visual field loss, and absence of other causes for the visual field loss. The inclusion criteria for the controls were IOP <21 mm Hg and cup-to-disc ratio ≤0.5. ASB10 exons were sequenced from both case and control DNA.
We sequenced the ASB10 gene in DNA from 228 cases and 319 controls, and used MYOC data that we have previously reported; additional data on these two genes came from the literature. The spatial distribution of causative mutations along MYOC is clearly asymmetric; the majority of causative changes are located in the third exon encoding the olfactomedin-related domain. Further examination of myocilin shows a cluster of causative charge changes in the olfactomedin-related domain that raises questions about whether that region of the protein might be especially sensitive to charge changes. While sequence variants in ASB10 are not confined to one region of the protein, asymmetry of the mutation distribution for the first exon of isoforms 1 and 2 and the alternative first exon of isoform 3 raises questions about the functional roles of different isoforms.
Sequence variants are expected to show similar spatial distribution along genes in cases and controls if the variants have no functional impact. The skewed distribution along the gene between cases and controls is consistent with the known causative role of MYOC in glaucoma. Differences in geographic localization of some ASB10 mutations raise questions about whether disease involvement might be specific to some isoforms. The distribution of sequence variants along these two genes between case and control populations will be presented and aspects of asymmetry will be discussed relative to the functional domains of the proteins.
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