New variants and in silico analyses in GRK1 associated Oguchi disease.
New variants and in silico analyses in GRK1 associated Oguchi disease.
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DOI：
10.1002/humu.24140
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发表时间：
2021-03
期刊：
影响因子：
3.9
通讯作者：
Inglehearn CF
中科院分区：
文献类型：
--
作者：
Poulter JA;Gravett MSC;Taylor RL;Fujinami K;De Zaeytijd J;Bellingham J;Rehman AU;Hayashi T;Kondo M;Rehman A;Ansar M;Donnelly D;Toomes C;Ali M;UK Inherited Retinal Disease Consortium, Genomics England Research Consortium;De Baere E;Leroy BP;Davies NP;Henderson RH;Webster AR;Rivolta C;Zeitz C;Mahroo OA;Arno G;Black GCM;McKibbin M;Harris SA;Khan KN;Inglehearn CF
G 蛋白偶联受体激酶 1 (GRK1) 的双等位基因突变会导致大口病，这是先天性静止性夜盲症 (CSNB) 的一种罕见亚型。本研究的目的是确定导致疾病的 GRK1 变异，并利用深入的生物信息学分析来评估它们对蛋白质结构的影响如何导致致病性。通过全基因组、全外显子组或聚焦外显子组测序对患者的基因组 DNA 进行测序。将已发表的和新颖的疾病相关变异与非疾病相关错义变异进行比较。然后使用一系列计算工具预测 GRK1 错义变异在蛋白质水平上的影响。我们鉴定了 12 个先前未发表的双等位基因疾病相关 GRK1 变异病例，其中包括 8 个新变异，并审查了所有 GRK1 疾病相关变异。进一步的基于结构的评分揭示了激酶结构域中错义变异的热点。此外，为了帮助未来的临床解释，我们确定了最能够区分疾病相关变异和非疾病相关变异的生物信息学工具。我们在大口病患者中发现了 GRK1 变异，并通过计算机模拟研究了致病变异如何阻碍蛋白质功能。在这项研究中，保尔特等人。将与大口病相关的视紫红质激酶 (GRK1) 突变数量从 13 个增加到 21 个。作者在一系列生物信息学预测软件中将疾病相关突变与可能的非致病性变异进行了比较。使用同源模型对突变进行的计算机分析表明，突变会导致三种潜在的疾病机制之一：蛋白质丢失、激酶功能丧失或异戊二烯化失败导致蛋白质错误定位。
Biallelic 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 disease causing GRK1 variants and use in‐depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure‐based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease‐causing variants may impede protein function in‐silico. In this study, Poulter et al. expand the number of mutations in Rhodopsin Kinase (GRK1), associated with Oguchi disease, from 13 to 21. The authors compare disease associated mutations with likely nonpathogenic variants in a range of bioinformatic prediction software. In silico analyses of the mutations, using a homology model, suggest mutations result in one of three potential mechanisms of disease: loss of protein, loss of kinase function or a failure of prenylation leading to mislocalisation of the protein.
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影响因子：
14.9
作者：
Mitchell AL;Attwood TK;Babbitt PC;Blum M;Bork P;Bridge A;Brown SD;Chang HY;El-Gebali S;Fraser MI;Gough J;Haft DR;Huang H;Letunic I;Lopez R;Luciani A;Madeira F;Marchler-Bauer A;Mi H;Natale DA;Necci M;Nuka G;Orengo C;Pandurangan AP;Paysan-Lafosse T;Pesseat S;Potter SC;Qureshi MA;Rawlings ND;Redaschi N;Richardson LJ;Rivoire C;Salazar GA;Sangrador-Vegas A;Sigrist CJA;Sillitoe I;Sutton GG;Thanki N;Thomas PD;Tosatto SCE;Yong SY;Finn RD
通讯作者：
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作者：
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Tesmer, John J. G.
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作者：
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Shendure, Jay
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作者：
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通讯作者：
Tesmer, John J. G.
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