Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa
Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa
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DOI：
10.1136/bjo.2004.063933
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发表时间：
2005-10-01
影响因子：
4.1
通讯作者：
Wissinger, B
中科院分区：
文献类型：
--
作者：
Schuster, A;Weisschuh, N;Wissinger, B
目的：鉴定常染色体显性色素性视网膜炎患者中新的或罕见的视紫红质基因突变并描述其临床表型。方法：通过 DNA 测序对索引患者的完整视紫红质基因进行突变筛查。突变特异性测定用于分离分析和对照筛选。通过临床评估，来自 5 个家庭的 8 名患者及其亲属被诊断为常染色体显性视网膜色素变性（adRP）。 结果：突变筛查发现了 5 种不同的视紫红质突变，其中包括 3 种新突变：Ser176Phe、Arg314fs16 和 Val20Gly，以及 2 种错义突变 Pro215Leu 和 Thr289Pro（仅在突变报告中报告过一次）。电生理学和心理物理学测试提供了来自每个基因型组的受试者中杆状系统受损以及锥状系统额外受影响的证据。与 Ser176Phe 表型相比，Arg314fs16 和 Val20Gly 突变受试者的视觉功能受到的影响较小。相反，Pro215Leu和Thr289Pro突变引起了非常严重的表型。结论：眼科研究结果支持疾病表达和结构改变之间的相关性：（1）细胞外/椎间盘内Val20Gly和细胞质Arg314fs16突变-轻度adRP表型； (2) Ser176Phe 突变——“主要是 1 型”疾病；(3) Pro215Leu 和 Thr289Pro 诱导的跨膜结构域 TM V 和 TM VII 的预测改变——严重表型。然而，相同基因型中表型表达的变异可能仍然是 RHO 突变的典型特征。
Aim: To identify novel or rare rhodopsin gene mutations in patients with autosomal dominant retinitis pigmentosa and description of their clinical phenotype.Methods: The complete rhodopsin gene was screened for mutations by DNA sequencing in index patients. Mutation specific assays were used for segregation analysis and screening for controls. Eight patients from five families and their relatives were diagnosed with autosomal dominant retinitis pigmentosa (adRP) by means of clinical evaluation.Results: Mutation screening identified five different rhodopsin mutations including three novel mutations: Ser176Phe, Arg314fs16, and Val20Gly and two missense mutations, Pro215Leu and Thr289Pro, that were only reported once in a mutation report. Electrophysiological and psychophysical testings provide evidence of an impaired rod system with additionally affected cone system in subjects from each genotype group. Visual function tended to be less affected in subjects with the Arg314fs16 and Val20Gly mutations than in the Ser176Phe phenotype. In contrast, Pro215Leu and Thr289Pro mutations caused a remarkably severe phenotype.Conclusion: The ophthalmic findings support a correlation between disease expression and structural alteration: ( 1) extracellular/intradiscal Val20Gly and cytoplasmic Arg314fs16 mutation - mild adRP phenotype; ( 2) Ser176Phe mutation -"mostly type 1'' disease; ( 3) predicted alteration of transmembrane domains TM V and TM VII induced by Pro215Leu and Thr289Pro - severe phenotype. However, variation of phenotype expression in identical genotypes may still be a typical feature of RHO mutations.