Abstract
USH2A is a common causal gene of retinitis pigmentosa (RP), a progressive blinding disease due to retinal degeneration. Genetic alterations in USH2A can lead to two types of RP, non-syndromic and syndromic RP, which is called Usher syndrome, with impairments of vision and hearing. The complexity of the genotype–phenotype correlation in USH2A-associated RP (USH2A-RP) has been reported. Genetic and clinical characterization of USH2A-RP has not been performed in Japanese patients. In this study, genetic analyses were performed using targeted panel sequencing in 525 Japanese RP patients. Pathogenic variants of USH2A were identified in 36 of 525 (6.9%) patients and genetic features of USH2A-RP were characterized. Among 36 patients with USH2A-RP, 11 patients had syndromic RP with congenital hearing problems. Amino acid changes due to USH2A alterations were similarly located throughout entire regions of the USH2A protein structure in non-syndromic and syndromic RP cases. Notably, truncating variants were detected in all syndromic patients with a more severe retinal phenotype as compared to non-syndromic RP cases. Taken together, truncating variants could contribute to more serious functional and tissue damages in Japanese patients, suggesting important roles for truncating mutations in the pathogenesis of syndromic USH2A-RP.
Highlights
Retinitis pigmentosa (RP) is the most common type of inherited retinal degenerative disease (IRD) and is clinically and genetically heterogeneous
P36 was not able to undergo Humphrey field analyzer (HFA) of the right eye due to low vision in the latest exam. These results suggest that 1. truncating USH2A variants contribute to hearing loss in USH2A-RP cases and 2. syndromic USH2A-RP patients had a more severe retinal disease with earlier onset and a more rapid decline in visual function than non-syndromic USH2A-RP patients
Molecular diagnosis was made in 287 of 525 RP cases (54.7%) and USH2A disease-causing variants were identified in 6.9% of RP patients (36 of 525 patients) in this cohort
Summary
Retinitis pigmentosa (RP) is the most common type of inherited retinal degenerative disease (IRD) and is clinically and genetically heterogeneous. Alterations in USH2A are responsible for Usher syndrome, which is the most common syndromic RP with sensorineural hearing loss [3]. USH2A plays important roles in the development and homeostasis of the inner ear and the retina [15,16] Because this protein belongs to cilial proteins, USH2A-associated diseases are categorized to ciliopathies [17,18]. We investigated the genetic and clinical characteristics focusing on the relationship between gene alterations and syndromic or non-syndromic USH2A-RP in Japanese patients. This study could provide additional evidence of race-specific genetic features in IRD and emphasize important roles of truncating variants, which lead to remnant protein functions for the pathogenesis of USH2A-RP
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