AUTHORS
James A Poulter, Molly S C Gravett, Rachel L Taylor, Kaoru Fujinami, Julie De Zaeytijd, James Bellingham, Atta Ur Rehman, Takaaki Hayashi, Mineo Kondo, Abdur Rehman, Muhammad Ansar, Dan Donnelly, Carmel Toomes, Manir Ali, UK Inherited Retinal Disease Consortium, Genomics England Research Consortium, Elfride De Baere, Bart P Leroy, Nigel P Davies, Robert H Henderson, Andrew R Webster, Carlo Rivolta, Christina Zeitz, Omar A Mahroo, Gavin Arno, Graeme C M Black, Martin McKibbin, Sarah A Harris, Kamron N Khan, Chris F Inglehearn
Hum Mutat. 2021 Feb;42(2):164-176. doi: 10.1002/humu.24140. Epub 2020 Nov 30.
ABSTRACT
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 We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants.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.
PMID:33252155 | PMC:PMC7898643 | DOI:10.1002/humu.24140
