Identification of a Novel Gene on 10q221 Causing Autosomal Dominant Retinitis Pigmentosa (adRP)

Authors

Stephen P Daiger, Human Genetics Center, School of Public Health and School of Medicine, The University of Texas Health Science Center, Houston TX
Lori S Sullivan, Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston TX
Sara J Bowne, Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston TX
Daniel C Koboldt, The Genome Institute, Washington University School of Medicine, St. Louis, MO
Susan H Blanton, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
Dianna K Wheaton, The Retina Foundation of the Southwest, Dallas, TX
Cheryl E Avery, Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston TX
Elizabeth D Cadena, Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston TX
Robert K Koenekoop, Montreal Children's Hospital, McGill University Health Center, Montreal, QC, H3H 1P3, Canada
Robert S Fulton, The Genome Institute, Washington University School of Medicine, St. Louis, MO
Richard K Wilson, The Genome Institute, Washington University School of Medicine, St. Louis, MO
George M Weinstock, Microbial Genomics, The Jackson Laboratory for Genomic Medicine, Farmington, CT
Richard A Lewis, Departments of Ophthalmology, Medicine, Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
David G Birch, The Retina Foundation of the Southwest, Dallas, TX

Publication Date

2016

Journal

Advances in Experimental Medicine and Biology, vol. 854

DOI

10.1007/978-3-319-17121-0_26

PMID

26427411

PMCID

PMC4906966

PubMedCentral® Posted Date

6-14-2016

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

no

Keywords

Base Sequence, Chromosomes, Human, Pair 10, DNA Mutational Analysis, Exome, Family Health, Female, Genes, Dominant, Genetic Predisposition to Disease, Genotype, Haplotypes, Hexokinase, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Missense, Pedigree, Retinitis Pigmentosa, Sequence Homology, Nucleic Acid

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.