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New variants and in silico analyses in GRK1 associated Oguchi disease
Author(s) -
Poulter James A.,
Gravett Molly S. C.,
Taylor Rachel L.,
Fujinami Kaoru,
De Zaeytijd Julie,
Bellingham James,
Rehman Atta Ur,
Hayashi Takaaki,
Kondo Mineo,
Rehman Abdur,
Ansar Muhammad,
Donnelly Dan,
Toomes Carmel,
Ali Manir,
De Baere Elfride,
Leroy Bart P.,
Davies Nigel P.,
Henderson Robert H.,
Webster Andrew R.,
Rivolta Carlo,
Zeitz Christina,
Mahroo Omar A.,
Arno Gavin,
Black Graeme C. M.,
McKibbin Martin,
Harris Sarah A.,
Khan Kamron N.,
Inglehearn Chris F.
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24140
Subject(s) - missense mutation , biology , exome sequencing , genetics , in silico , exome , loss function , computational biology , mutation , bioinformatics , gene , phenotype
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 We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants.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.