title: A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Linkage analysis followed by whole-exome sequencing was performed. Stringent variant filtering and prioritization was carried out to identify the causative mutation.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States.
authors.forename: Vera
authors.initials: V
authors.lastname: Lyubasyuk
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States.
authors.forename: Frances
authors.initials: F
authors.lastname: Wu
authors.affiliation: Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wen
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, United States.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.affiliation: Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States.
authors.forename: Danni
authors.initials: D
authors.lastname: Lin
authors.affiliation: Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States.
authors.forename: Susanna
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States Veterans Administration Healthcare System, San Diego, California, United States.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, United States The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D004247:DNA; C472074:HK1 protein, human; D006593:Hexokinase
keywords: HK1; autosomal dominant retinitis pigmentosa (adRP); hexokinase; next-generation sequencing (NGS); novel disease-causing gene