Mutation Analysis of the USH2A Gene in Japanese Patients with Autosomal Recessive Retinitis Pigmentosa

Abstract

Purpose: Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease with autosomal recessive (ar), autosomal dominant, or X-linked inheritance. The Usher syndrome 2A (USH2A) gene, which accounts for approximately 74-90% of Usher syndrome type 2 (USH2) cases, is one of the major RP causative genes among the European and North American populations.

Methods: To identify disease-causing USH2A gene mutations in Japanese RP patients, all 73 exons were screened for mutations by polymerase chain reaction amplification. A total of 100 unrelated Japanese RP patients with no systemic manifestation were identified, with the exclusion of families with obvious autosomal dominant inheritance. Of these 100 patients, 18 with very likely pathogenic mutations in the eyes shut homolog (EYS) gene were excluded, and the other 82 were included in the study. The ophthalmological data of 13 previously reported unrelated Japanese USH2 patients with USH2A mutations were also collected. The phenotype analysis was based on ophthalmic examination and audiograms.

Results: The mutation analysis of the USH2A gene revealed that there were 5 very likely pathogenic mutations in 4 patients (4%) and that one of them did not have another possible pathogenic mutation. These very likely pathogenic mutations consisted of a deletion mutation, 2 splicing mutations, and 2 missense mutations. In addition, we also identified 3 possible pathogenic mutations in 3 individual patients. All the 4 patients with 1 or 2 very likely pathogenic mutations and 13 USH2 patients with USH2A mutations exhibited typical clinical features of RP, with the central visual acuity preserved relatively well up to their thirties.

Conclusions: The observed prevalence of distinct USH2A gene mutations is approximately 4% among Japanese arRP patients, and the spectrum of the USH2A gene mutations differs largely between Japanese patients and previously reported European or North American populations. The USH2A-associated RP phenotype is typical and fairly homogeneous in most patients.

Keywords: 696 retinal degenerations: hereditary • 537 gene screening • 539 genetics