Mutations In The USH2A Gene Are A Frequent Cause Of Recessive Nonsyndromic Retinitis Pigmentosa As Well As Usher Syndrome Type II

Abstract

Abstract: : Purpose: To measure the proportion of patients with nonsyndromic recessive retinitis pigmentosa (RP) or with Usher syndrome type II who have mutations in the USH2A gene. Methods: The exons of the USH2A gene are amplified, some individually and others in small sets, from the leukocyte DNA of 221 unrelated patients with nonsyndromic recessive RP, 290 with nonsyndromic isolate RP, 98 with Usher syndrome type II, and 190 normal controls. Amplified DNA fragments are scanned for mutations using single-strand conformation analysis (SSCP). Variant DNA fragments are directly sequenced. Results: We began this study by analyzing the region of the USH2A gene in which a mutation (Cys759Phe, TGC to TTC) causing nonsyndromic recessive RP was previously reported. After evaluating only about 5% of the gene, including this region, we have found likely pathogenic mutations in 18 patients with recessive RP (8%), 38 patients with isolate RP (13%), and 25 patients with Usher syndrome type II (24%). The allele frequency of the Cys759Phe mutation alone is 2.9% among recessive RP, 3.6% among isolate RP, 1.0% among Usher type II, and 0.3% among normal controls. The mutation Glu767(1-bp del) (2299delG) was also evaluated and found to be far more frequent among patients with Usher type II (allele frequency in that group = 10.7%) vs. patients with nonsyndromic RP (allele frequency = 2.4%), (p < 0.0001), or vs. normal controls (allele frequency = 0%) (p = 0.0004). Four novel mutations were encountered: Gly691Ter (TGC to TGA) and Gly700(1-bp del) (GGG to GG-) in one Usher syndrome patient each, and IVS12 -1 G≷C and Gln765(1-bp del) (CAG to -AG), in two patients with isolate nonsyndromic RP. A previously reported mutation, Gly713Arg (GGC to CGC), appeared not to be pathogenic since it did not cosegregate with RP in one family. Conclusion: Extrapolating from the partial screen performed to date, it appears that mutations in USH2A may be responsible for well over 12% of all cases of recessive RP (combining our data from recessive, isolate, and Usher type II cases). Since these genetic categories account for over half of all RP cases in North America, our data suggest that USH2A is likely to account for the highest proportion of cases of any RP gene.

Keywords: 562 retinal degenerations: hereditary • 480 mutations • 420 genetics