Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population.
Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population.
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DOI：
10.1371/journal.pone.0031036
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hotta Y
中科院分区：
文献类型：
--
作者：
Hosono K;Ishigami C;Takahashi M;Park DH;Hirami Y;Nakanishi H;Ueno S;Yokoi T;Hikoya A;Fujita T;Zhao Y;Nishina S;Shin JP;Kim IT;Yamamoto S;Azuma N;Terasaki H;Sato M;Kondo M;Minoshima S;Hotta Y
视网膜色素变性（RP）是一种高度异质性的遗传疾病，包括常染色体隐性遗传（ar）、常染色体显性遗传（ad）和X连锁遗传。最近，arRP已与EYS（Eyes shut homolog）突变相关，EYS是该疾病的主要致病基因。本研究旨在确定100例日本arRP患者的EYS突变谱和频率。为了确定EYS突变的患病率，通过聚合酶链反应扩增筛选所有EYS外显子的突变，并进行序列分析。我们在EYS中检测到67个序列改变，其中21个是新的。其中，7个非常可能是致病性突变，6个可能是致病性突变，54个预测为非致病性序列改变。在我们的研究中，观察到的不同EYS突变的最低患病率为18%（18/100，包括9名患者有2个非常可能的致病突变，其余9名患者只有一个这样的突变）。在这些突变中，在16例患者中发现了2个新的截短突变，c.4957_4958insA（p.S1653KfsX2）和c.8868C>A（p.Y2956X），占突变等位基因的57.1%（20/35）。虽然这2个截断突变没有检测到日本患者adRP或Leber的先天性黑蒙，我们发现他们在韩国arRP患者。与日本arRP结果相似，c.4957_4958insA突变的检出率高于c.8868C>A突变。在我们的研究中，18%的估计患病率非常可能的致病性突变表明，在日本人群中的arRP的发病机制中，EYS的主要参与。100例日本患者的EYS突变谱，包括13种不同的非常可能和可能的致病性突变，与先前报道的非亚洲人群患者的突变谱有很大不同。因此，筛查EYS基因中的c.4957_4958insA和c.8868C>A突变可能对日本RP患者的基因检测和咨询非常有效。
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.
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