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.

Keywords: Autosomal dominant retinitis pigmentosa; Founder effect; Hexokinase; Linkage mapping; Next-generation sequencing; Retinitis pigmentosa.

Fig. 26.1

Pedigrees of five adRP families with the HK1 Glu847Lys missense mutation. Squares males; circles females; blackened symbols affected. All individuals with an HK1 genotype indicated were tested. HK1^−/+, heterozygous for the mutation; HK1^+/+, homozygous for the mutation; HK1^−/−, no mutation

Fig. 26.2

Chromosomal haplotypes in cis to the HK1 Glu847Lys mutation, including two distinct haplotypes in the homozygous individual in UTAD003, and an unaffected, at-risk individual in UTAD952. Exons of HK1 and distances (in kb) of chromosome 10q21.1 are shown at the top of the figure. SNP and markers defining the haplotype are listed at bottom. Observed SNP alleles are listed in each bar. Dark gray region of bars, shared SNP alleles; light gray region of bars, alleles not shared. The shared haplotype across all families is 450 kb ( top arrows), whereas the shortest region of linkage overlap, including the unaffected member of UTAD952, is 55 kb ( second arrows)