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B. Jian-Seyed-Ahmadi, C. Rivolta, J.A. Keene, E.L. Berson, T.P. Dryja; All-Exon Screen of the Ush2a Gene in Recessive Nonsyndromic Retinitis Pigmentosa and Usher Syndrome Type II . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2315.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To measure the proportion of patients with nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) and with Usher syndrome type II (Usher-II) who have mutations in the USH2A gene and to tabulate the types of mutations found. Methods: All the coding exons of the USH2A gene are being amplified from the leukocyte DNA of 156 unrelated patients with ARRP and 129 with Usher-II. Amplified DNA fragments are scanned for mutations using single-strand conformation analysis and direct sequencing. Results: To date 28 out of 31 exon fragments have been evaluated. We identified 10 different, likely pathogenic, sequence variants in 28 ARRP patients, including 7 missense, 2 frameshift, and 1 nonsense change. Among 59 patients with Usher-II, we found 22 different sequence variants (8 missense, 11 frameshift, 3 nonsense). Segregation analyses to evaluate the possible pathogenicity of some of these sequence variations are in progress. We also found 4 intron changes and 8 exon polymorphisms (6 of which were isocoding variations); all of these are interpreted as unlikely to be pathogenic. Of the 33 presumed mutant alleles found in ARRP patients, 18 were C759F, 6 were D644V, 2 were L1047V, and there was 1 instance of each of 7 other changes. Three ARRP patients were homozygotes for C759F, 1 patient was a compound heterozygote (C759F/E767fs), and 12 patients (8%) had C759F on one allele and no detected change on the other allele. The C759F allele was found in 2 patients with Usher-II; in neither of these 2 patients was a change in the other allele found. The most common variant found in Usher-II patients was E767fs (2299 del G) which accounted for 29/68 variant alleles. Only 17% of the ARRP patients with an USH2A variant had 2 variants detected (presumably one on each allele); only 20% of Usher-II patients with an USH2A variant had 2 variants detected. Conclusions: Based on our evaluation of about 90% of the gene so far, USH2A sequence variants that are likely to be pathogenic were found in about 18% of cases of ARRP (3.2% with 2 mutations + 14.3% with 1 mutation), and in about 46% of cases of Usher-II (9.3% with 2 mutations + 36.4% with 1 mutation). Further studies are needed to explain the large proportion of patients with a presumed mutation in only one allele. To our knowledge this is the first report of USH2A variants besides C759F (such as D644V) associated with nonsyndromic ARRP.
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