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B. Jian Seyedahmadi, E.L. Berson, T.P. Dryja; USH3A mutations in patients with a prior diagnosis of Usher syndrome type I, Usher syndrome type II, and nonsyndromic recessive retinitis pigmentosa . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4726.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To establish the frequency of USH3A mutations among patients with recessive retinitis pigmentosa with or without self–reported hearing loss. Methods: Fragments of the USH3A gene were amplified, some individually and others in small sets, from the leukocyte DNA of 72 unrelated patients with a prior diagnosis of Usher syndrome type I (USH1), 218 with Usher syndrome type II (USH2), and 166 with nonsyndromic autosomal recessive retinitis pigmentosa (ARRP). Patients with known mutations in the USH2A gene were not excluded from this study. Amplified DNA fragments were scanned for mutations using direct sequencing. Results: A partial screen to date of 72 USH1 patients revealed 3 with homozygous USH3A mutations (2 with Tyr63End and 1 with Asn48Lys). All 3 of these patients reported profound deafness since early childhood and one reported delayed onset of walking (age 3 years) presumably due to vestibular dysfunction. An analysis of 218 USH2 patients found 13 (6%) with USH3A mutations. All were homozygotes: 10 with Asn48Lys, 2 with Tyr63End, and 1 with Tyr176End. A partial screen to date of 166 nonsyndromic ARRP patients revealed 2 index patients who were homozygotes for USH3A mutations (both with Asn48Lys). These 2 patients reported no hearing loss at their last clinical evaluations at ages of 32 and 39 years. No compound heterozygotes and no cases with only one mutant allele have been identified. All 4 patients who were Tyr63End homozygotes were also homozygotes for a rare variant in intron 1 (IVS1+48T>C); no other patients carried this intron change. The linkage disequilibrium between this intron change and Tyr63End suggests that all patients with this mutation descend from a common ancestor. Conclusions: USH3A mutations can cause recessive retinitis pigmentosa with or without reported hearing loss. Due to the wide range of hearing acuity, patients with USH3A mutations may have a clinical diagnosis of Usher type I, Usher type II, or nonsyndromic recessive RP. Extrapolating from the partial screen performed to date, it appears that the USH3A gene accounts for about 6% of all cases of Usher syndrome (combining our data from type I and II cases). It may be necessary to analyze the USH3A gene to identify which patients with apparent nonsyndromic ARRP are at high risk for hearing loss later in life.
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