New variants and in silico analyses in GRK1 associated Oguchi disease
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., 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., Black GC., Hall G., Ingram S., Sergouniotis P., Hardcastle AJ., Michaelides M., Pontikos N., Cheetham M., Fiorentino A., Smith CEL., Downes S., Yu J., van Heyningen V., Ambrose JC., Arumugam P., Baple EL., Bleda M., Boardman-Pretty F., Boissiere JM., Boustred CR., Brittain H., Caulfield MJ., Chan GC., Craig CEH., Daugherty LC., de Burca A., Devereau A., Elgar G., Foulger RE., Fowler T., Furió-Tarí P., Hackett JM., Halai D., Hamblin A., Henderson S., Holman JE., Hubbard TJP., Ibáñez K., Jackson R., Jones LJ., Kasperaviciute D., Kayikci M., Lahnstein L., Lawson K., Leigh SEA., Leong IUS., Lopez FJ., Maleady-Crowe F., Mason J., McDonagh EM., Moutsianas L., Mueller M., Murugaesu N., Need AC., Odhams CA., Patch C., Perez-Gil D., Polychronopoulos D., Pullinger J., Rahim T., Rendon A., Riesgo-Ferreiro P., Rogers T., Ryten M., Savage K., Sawant K., Scott RH., Siddiq A., Sieghart A., Smedley D., Smith KR., Sosinsky A.
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 We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants.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.