Two Novel Mutations in the EYS Gene Are Possible Major Causes of Autosomal Recessive Retinitis Pigmentosa in the Japanese Population

Katsuhiro Hosono,Yasuhiko Hirami,Shinsei Minoshima,In Taek Kim,Yang Zhao,Jae Pil Shin,Mineo Kondo,Chie Ishigami,Sachiko Nishina,Taichi Fujita,Hiroshi Nakanishi,Dong Ho Park,Shinji Ueno,Yoshihiro Hotta,Shuichi Yamamoto,Akiko Hikoya,Noriyuki Azuma,Hiroko Terasaki,Masayo Takahashi,Tadashi Yamaguchi ,M Sato

doi:10.1371/journal.pone.0031036

Abstract

Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease including autosomal recessive (ar), autosomal dominant (ad), and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog), which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation). Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2) and c.8868C>A (p.Y2956X), were identified in 16 patients and accounted for 57.1% (20/35 alleles) of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing and counseling of RP patients in Japan.

Highlights

Retinitis pigmentosa (RP [MIM 268000]) is a highly heterogeneous genetic disease characterized by night blindness and visual field constriction leading to severe visual impairment
We found 2 novel truncating eyes shut homolog (EYS) gene mutations that were surprisingly related to 16% of Japanese arRP patients, but were not detected in Japanese patients with either adRP or Leber’s congenital amaurosis (LCA [MIM204000], the earliest onset and most severe form of hereditary retinal dystrophy with several clinical features overlapping with those of RP)
The very likely pathogenic mutations consisted of 3 truncating mutations, 1 deletion mutation, 2 missense mutations, and 1 previously described mutation (Fig. 1, Table 1, and Table 2)

Summary

Introduction

Retinitis pigmentosa (RP [MIM 268000]) is a highly heterogeneous genetic disease characterized by night blindness and visual field constriction leading to severe visual impairment. The disease appears with different modes of inheritance including autosomal recessive (ar), autosomal dominant (ad), and X-linked, and currently over half of cases are isolated in Japan. 53 causative genes and 7 loci of RP have been identified (http://www.sph.uth.tmc.edu/Retnet/), including the eyes shut homolog (EYS) gene encoding an ortholog of Drosophila spacemaker (spam), a protein essential for photoreceptor morphology. EYS gene mutations, primarily truncating and some missense mutations, have been detected in arRP families of different ancestral origin and have reported to account for 5–16% of arRP [3–6]. Most gene mutations (e.g., RHO, PRPH2, PRPF31, RP1, and IMPDH1) have been found in Japanese patients with adRP, with few reports describing mutations in arRP [7,8]. The genes causing arRP in most Japanese families have yet to be identified

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Conclusion