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 We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants.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.
Highlights
The first member of the G protein‐coupled receptor kinase (GRK) family was discovered when enzymatic activity was observed in rod membranes that phosphorylated rhodopsin in a light‐dependent manner (Kuhn & Dreyer, 1972)
Using a combined genetics and structural biology approach we have identified individuals with Oguchi disease due to biallelic G‐Protein coupled receptor kinase 1 (GRK1) variants and inferred the likely functional consequences of these and other published variants
We identified eight new disease associated variants, taking the total number of GRK1 variants associated with
Summary
The first member of the G protein‐coupled receptor kinase (GRK) family was discovered when enzymatic activity was observed in rod membranes that phosphorylated rhodopsin in a light‐dependent manner (Kuhn & Dreyer, 1972). Light‐activated rhodopsin is phosphorylated multiple times by GRK1, followed by binding of Arrestin‐1 to activated‐phosphorylated rhodopsin to block further transducin activation by steric exclusion (Krupnick et al, 1997; Wilden et al, 1986). Failure of this process results in a build‐up of activated rhodopsin, which continues to activate the phototransduction cascade, shutting off circulating current in the rod photoreceptors, rendering them unable to respond electrically to light. Activated cone opsin is likely to be more reliant on GRK7 than GRK1 phosphorylation, as both enzymes are expressed in cones, loss of GRK1 function has minimal impact on human photopic vision
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