A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa

• Published in: Investigative ophthalmology & visual science 2014-11, Vol.55 (11), p.7159-7164
• Main Authors: Wang, Feng, Wang, Yandong, Zhang, Bin, Zhao, Li, Lyubasyuk, Vera, Wang, Keqing, Xu, Mingchu, Li, Yumei, Wu, Frances, Wen, Cindy, Bernstein, Paul S, Lin, Danni, Zhu, Susanna, Wang, Hui, Zhang, Kang, Chen, Rui
• Format: Article
• Language: English
• Subjects: Adolescent; Child; Child, Preschool; DNA - genetics; DNA Mutational Analysis; Female; Genes, Dominant; Genetic Linkage; Genetic Predisposition to Disease; Heterozygote; Hexokinase - genetics; Hexokinase - metabolism; Humans; Male; Mutation, Missense; Pedigree; Phenotype; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - metabolism; Retinitis Pigmentosa - pathology; Young Adult
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.14-15520

Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 60 causative genes known to date. Nevertheless, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing genes are yet to be identified. In this study, we aimed to identify the causative mutation for a large autosomal dominant RP (adRP) family with negative results from known retinal disease gene screening. Linkage analysis followed by whole-exome sequencing was performed. Stringent variant filtering and prioritization was carried out to identify the causative mutation. Linkage analysis identified a minimal disease region of 8 Mb on chromosome 10 with a peak parametric logarithm (base 10) of odds (LOD) score of 3.500. Further whole-exome sequencing identified a heterozygous missense mutation (NM_000188.2:c.2539G>A, p.E847K) in hexokinase 1 (HK1) that segregated with the disease phenotype in the family. Biochemical assays showed that the E847K mutation does not affect hexokinase enzymatic activity or the protein stability, suggesting that the mutation may impact other uncharacterized function or result in a gain of function of HK1. Here, we identified HK1 as a novel causative gene for adRP. This is the first report that associates the glucose metabolic pathway with human retinal degenerative disease, suggesting a potential new disease mechanism.