title: Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP).
abstract: Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites.
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas HSC, 1200 Pressler St., Houston, TX, 77030, USA. Stephen.P.Daiger@uth.tmc.edu.|Ruiz Department of Ophthalmology and Visual Science, Medical School, The University of Texas Health Science Center, Houston, TX, 77030, USA. Stephen.P.Daiger@uth.tmc.edu.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas HSC, 1200 Pressler St., Houston, TX, 77030, USA. lori.s.sullivan@uth.tmc.edu.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas HSC, 1200 Pressler St., Houston, TX, 77030, USA. sara.j.bowne@uth.tmc.edu.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA. dkoboldt@genome.wustl.edu.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. sblanton@med.miami.edu.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.affiliation: The Retina Foundation of the Southwest, Dallas, TX, 75231, USA. dwheaton@retinafoundation.org.
authors.forename: Dianna K
authors.initials: DK
authors.lastname: Wheaton
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas HSC, 1200 Pressler St., Houston, TX, 77030, USA. cheryl.e.avery@uth.tmc.edu.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Avery
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas HSC, 1200 Pressler St., Houston, TX, 77030, USA. elizabeth.d.cadena@uth.tmc.edu.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Cadena
authors.affiliation: McGill Ocular Genetics Laboratory, Departments of Paediatric Surgery, Human Genetics and Ophthalmology, Montreal Children's Hospital, McGill University Health Center, Montreal, QC, H3H 1P3, Canada. robkoenekoop@hotmail.com.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA. rfulton22@wustl.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA. rwilson@wustl.edu.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Microbial Genomics, The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA. george.weinstock@jax.org.
authors.forename: George M
authors.initials: GM
authors.lastname: Weinstock
authors.affiliation: Departments of Ophthalmology, Medicine, Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. rlewis@bcm.tmc.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.affiliation: The Retina Foundation of the Southwest, Dallas, TX, 75231, USA. dbirch@retinafoundation.org.
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
mesh_terms: D001483:Base Sequence; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006593:Hexokinase / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
chemical_list: C472074:HK1 protein, human; D006593:Hexokinase
keywords: Autosomal dominant retinitis pigmentosa; Founder effect; Hexokinase; Linkage mapping; Next-generation sequencing; Retinitis pigmentosa