Identification of Novel Mutations in the Ortholog of Drosophila Eyes Shut Gene (EYS) Causing Autosomal Recessive Retinitis Pigmentosa
Identification of Novel Mutations in the Ortholog of Drosophila Eyes Shut Gene (EYS) Causing Autosomal Recessive Retinitis Pigmentosa
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DOI：
10.1167/iovs.09-5109
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发表时间：
2010-08-01
影响因子：
4.4
通讯作者：
Bhattacharya, Shomi S.
中科院分区：
文献类型：
--
作者：
Abd El-Aziz, Mai M.;O'Driscoll, Ciara A.;Bhattacharya, Shomi S.
目的.最近，一个新的基因被克隆为常染色体隐性视网膜色素变性（arRP），EYS，6 q12。本研究旨在确定195名无血缘关系的常染色体隐性和常染色体显性RP（adRP）患者的EYS突变谱和频率。方法。所有病例都有完整的眼科检查，RP的临床诊断是基于视力，眼底照相和视网膜电图的结果。从所有参与者提取的DNA进行分子遗传学分析，需要扩增的编码区和外显子-内含子边界的EYS的聚合酶链反应，然后直接测序。进行生物信息学分析以研究所鉴定的突变对蛋白质结构和功能的影响。在10名不相关的arRP患者中，在EYS内发现了11个新的错义、无义和剪接位点突变，可能的等位基因频率为11%。然而，在adRP组中未观察到突变。此外，还发现了53个单核苷酸多态性（SNPs），其中12个以前未报道过。生物信息学分析显示，所有突变在其他物种中高度保守和/或涉及蛋白质结构上的重要结构域。在一个具有双杂合突变的家族中也观察到家族内表型变异。这是第一个报告的分子遗传学分析EYS在一个队列无关的英国和中国的RP患者。这些结果进一步证实了最初的假设，即EYS是隐性RP的主要致病基因，并强调了不同类型的突变在破坏EYS功能中的作用。（Invest Ophthalmol维斯科学。2010; 51：4266-4272）DOI：10.1167/iovs.09-5109
PURPOSE. Recently, a novel gene was cloned for autosomal recessive retinitis pigmentosa (arRP), EYS, on 6q12. This study was conducted to determine the spectrum and frequency of EYS mutations in 195 unrelated patients with autosomal recessive and autosomal dominant RP (adRP).METHODS. All cases had a complete ophthalmic examination, and the clinical diagnosis of RP was based on visual acuity, fundus photography, and electroretinography findings. The DNA extracted from all participants was subjected to molecular genetic analysis entailing amplification of the coding regions and exon-intron boundaries of EYS by polymerase chain reaction, followed by direct sequencing. Bioinformatics analysis was undertaken to study the effect of the identified mutations on protein structure and function.RESULTS. Eleven novel missense, nonsense, and splice site mutations were identified within EYS in 10 unrelated arRP patients, with probable allele frequency of 11%. However, no mutations were observed in the adRP panel. In addition, 53 single-nucleotide polymorphisms (SNPs) were found, of which 12 were previously unreported. Bioinformatics analyses revealed that all mutations were highly conserved across other species and/or involved important domains on protein structure. Intrafamilial phenotypic variability was also observed in a family with double heterozygous mutations.CONCLUSIONS. This is the first report of molecular genetic analysis of EYS in a cohort of unrelated British and Chinese patients with RP. The results further the initial hypothesis that EYS is a major causative gene for recessive RP and emphasize the role of different types of mutations in disrupting the function of EYS. (Invest Ophthalmol Vis Sci. 2010; 51:4266-4272) DOI:10.1167/iovs.09-5109