New pathogenic variants and insights into pathogenic mechanisms in GRK1-related Oguchi disease
New pathogenic variants and insights into pathogenic mechanisms in GRK1-related Oguchi disease
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GRK1相关大口病的新致病变异和致病机制的见解
DOI：
10.1101/2020.02.20.936880
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Poulter J
中科院分区：
文献类型：
--
作者：
Poulter J
目的G蛋白偶联受体激酶1（GRK1）基因的双等位基因突变导致Oguchi病，这是一种罕见的先天性静止性夜盲症（CSNB）亚型。本研究的目的是确定致病性GRK1变体，并使用深入的生物信息学分析，以评估其对蛋白质结构的影响如何可能导致pathogenicity.MethodsPatients的基因组DNA测序全基因组，全外显子组或集中外显子组测序。将已发表的和新的致病性变体与非疾病相关的错义变体进行比较。的影响ofGRK1错义变体在蛋白质水平上，然后预测使用一系列的计算tools.ResultsWe确定了11个以前未发表的情况下，双等位基因致病GRK1变体，包括7个新的变体，并审查allGRK1致病变体。进一步基于结构的评分揭示了激酶结构域中错义变体的热点。此外，为了帮助未来的临床解释，我们确定了最能区分致病性和非致病性variants.ConclusionWe的生物信息学工具确定了新的GRK1致病性变异的Oguchi病患者和调查如何致病的变异可能会阻碍蛋白质的功能，致病性的机制提供了新的见解。迄今为止描述的所有致病性GRK1变体都已整理到莱顿开放变异数据库（http：//dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1）中。
PurposeBiallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify pathogenic GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity.MethodsPatients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Pathogenic variants, published and novel, were compared to nondisease associated missense variants. The impact ofGRK1missense variants at the protein level were then predicted using a series of computational tools.ResultsWe identified eleven previously unpublished cases with biallelic pathogenic GRK1 variants, including seven novel variants, and reviewed allGRK1pathogenic variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. Additionally, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate pathogenic from non-pathogenic variants.ConclusionWe identified newGRK1pathogenic variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function, giving new insights into the mechanisms of pathogenicity. All pathogenic GRK1 variants described to date have been collated into a Leiden Open Variation Database (http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1).
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Oguchi 病的一种变异形式定位于与 GRK1 基因部分缺失相关的 13q34。
影响因子：
2.2
作者：
Zhang,Qingjiong;Zulfiqar,Fareeha;Riazuddin,SAmer;Xiao,Xueshan;Yasmeen,Afshan;Rogan,PeterK;Caruso,Raphael;Sieving,PaulA;Riazuddin,Sheikh;Hejtmancik,JFielding
通讯作者：
Hejtmancik,JFielding
影响因子：
4.6
作者：
Jespersgaard, Cathrine;Fang, Mingyan;Gronskov, Karen
通讯作者：
Gronskov, Karen
影响因子：
4.8
作者：
Komolov KE;Benovic JL
通讯作者：
Benovic JL
影响因子：
3.4
作者：
Teke MY;Citirik M;Kabacam S;Demircan S;Alikasifoglu M
通讯作者：
Alikasifoglu M
影响因子：
13.7
作者：
Hayashi, Takaaki;Gekka, Tamaki;Kitahara, Kenji
通讯作者：
Kitahara, Kenji