title: A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa.
abstract: OBJECTIVE
  To identify the cause of retinitis pigmentosa (RP) in UTAD003, a large, six-generation Louisiana family with autosomal dominant retinitis pigmentosa (adRP).
  
  
  METHODS
  A series of strategies, including candidate gene screening, linkage exclusion, genome-wide linkage mapping, and whole-exome next-generation sequencing, was used to identify a mutation in a novel disease gene on chromosome 10q22.1. Probands from an additional 404 retinal degeneration families were subsequently screened for mutations in this gene.
  
  
  RESULTS
  Exome sequencing in UTAD003 led to identification of a single, novel coding variant (c.2539G>A, p.Glu847Lys) in hexokinase 1 (HK1) present in all affected individuals and absent from normal controls. One affected family member carries two copies of the mutation and has an unusually severe form of disease, consistent with homozygosity for this mutation. Screening of additional adRP probands identified four other families (American, Canadian, and Sicilian) with the same mutation and a similar range of phenotypes. The families share a rare 450-kilobase haplotype containing the mutation, suggesting a founder mutation among otherwise unrelated families.
  
  
  CONCLUSIONS
  We identified an HK1 mutation in five adRP families. Hexokinase 1 catalyzes phosphorylation of glucose to glucose-6-phosphate. HK1 is expressed in retina, with two abundant isoforms expressed at similar levels. The Glu847Lys mutation is located at a highly conserved position in the protein, outside the catalytic domains. We hypothesize that the effect of this mutation is limited to the retina, as no systemic abnormalities in glycolysis were detected. Prevalence of the HK1 mutation in our cohort of RP families is 1%.
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, Texas, United States.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.affiliation: The Genome Institute at Washington University, St. Louis, Missouri, United States.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, Texas, United States.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Lang
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, Texas, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cadena
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, Texas, United States.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Avery
authors.affiliation: Departments of Ophthalmology, Medicine, Pediatrics, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.affiliation: The Retina Foundation of the Southwest, Dallas, Texas, United States.
authors.forename: Kaylie
authors.initials: K
authors.lastname: Webb-Jones
authors.affiliation: The Retina Foundation of the Southwest, Dallas, Texas, United States.
authors.forename: Dianna H
authors.initials: DH
authors.lastname: Wheaton
authors.affiliation: The Retina Foundation of the Southwest, Dallas, Texas, United States.
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.affiliation: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics, and Ophthalmology, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Razck
authors.initials: R
authors.lastname: Coussa
authors.affiliation: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics, and Ophthalmology, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Huanan
authors.initials: H
authors.lastname: Ren
authors.affiliation: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics, and Ophthalmology, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Chakarova
authors.affiliation: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics, and Ophthalmology, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Texas Health Science Center, Houston, Texas, United States.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Garcia
authors.affiliation: The Genome Institute at Washington University, St. Louis, Missouri, United States.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: The Genome Institute at Washington University, St. Louis, Missouri, United States.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: The Genome Institute at Washington University, St. Louis, Missouri, United States.
authors.forename: George M
authors.initials: GM
authors.lastname: Weinstock
authors.affiliation: Human Genetics Center, University of Texas Health Science Center, Houston, Texas, United States Department of Ophthalmology and Visual Sciences, University of Texas Health Science Center, Houston, Texas, United States.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D005799:Genes, Dominant; D008040:Genetic Linkage; D006239:Haplotypes; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D004247:DNA; C472074:HK1 protein, human; D006593:Hexokinase
keywords: hexokinase; inherited retinal dystrophy; retinitis pigmentosa