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C.M. Zaremba, W. Wiszniewski, R.A. Lewis, J.R. Lupski; Identification of ABCA4 Regulatory Mutations in Stargart Families . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1794.
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Purpose: Stargart disease (STGD1) is an autosomal recessive retinal dystrophy characterized by progessive atrophy of the central retina and RPE, accumulation of drusen in the mid–peripheral RPE, sequential atrophy of the optic disc, and a dark choroids sign on fluorescein angiography. Current studies, in addition to direct sequencing, have begun screening for ABCA4 mutant alleles using a microarray–based assay focused specifically on the coding region, leaving a substantial fraction of mutant alleles unaccounted for. These methods, while effective, limit the ability to detect all possible mutations. Therefore, the purpose of this study is to identify potential regulatory mutations found in the non–coding regions of ABCA4. Methods: Using a commercially available microarray, ABCR–400, we screened a cohort of 192 families with STGD. Families were then subjected to haplotype analysis using markers spanning the ABCA4 genomic region: D1S435, D1S2868, D1S2793, and D1S206. Additionally, a ∼2 kb segment upstream of the 5’ UTR was analyzed for mutations in predicted regulatory regions. Results: We identified two distinct groups of families possessing zero (16 families; 8.33%) or one (40 families; 20.8%) coding region alteration in ABCA4. Preliminary data regarding segregation analysis demonstrated that in 7 out of 16 (43.8%) families bearing no ABCA4 alterations, STGD patients shared the same haplotypes at the disease locus. Conclusions: These data suggest that a substantial fraction of mutations are undetected in patients with STGD. We conclude that the majority of these mutations may reside in the non–coding region of ABCA4 or potentially at other loci.
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