Identification of a novel gene on 10q22.1 causing autosomal dominant retinitis pigmentosa (adRP)

Stephen P. Daiger, Lori S. Sullivan, Sara J. Bowne, Daniel C. Koboldt, Susan H Blanton, Dianna K. Wheaton, Cheryl E. Avery, Elizabeth D. Cadena, Robert K. Koenekoop, Robert S. Fulton, Richard K. Wilson, George M. Weinstock, Richard A. Lewis, David G. Birch

Research output: Chapter in Book/Report/Conference proceedingChapter

4 Citations (Scopus)

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 sixgeneration 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 widelyexpressed 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.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer New York LLC
Pages193-200
Number of pages8
Volume854
DOIs
StatePublished - Oct 1 2016

Publication series

NameAdvances in Experimental Medicine and Biology
Volume854
ISSN (Print)00652598
ISSN (Electronic)22148019

Fingerprint

Retinitis Pigmentosa
Genes
Hexokinase
Mutation
Chromosomes
Chromosome Mapping
Haplotypes
Phosphorylation
Exome
X-Linked Genes
Glycolysis
Missense Mutation
Genetic Recombination
Catalytic Domain
Glucose
Genome
Testing
Population

Keywords

  • Autosomal dominant retinitis pigmentosa
  • Founder effect
  • Hexokinase
  • Linkage mapping
  • Next-generation sequencing
  • Retinitis pigmentosa

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Daiger, S. P., Sullivan, L. S., Bowne, S. J., Koboldt, D. C., Blanton, S. H., Wheaton, D. K., ... Birch, D. G. (2016). Identification of a novel gene on 10q22.1 causing autosomal dominant retinitis pigmentosa (adRP). In Advances in Experimental Medicine and Biology (Vol. 854, pp. 193-200). (Advances in Experimental Medicine and Biology; Vol. 854). Springer New York LLC. https://doi.org/10.1007/978-3-319-17121-0_26

Identification of a novel gene on 10q22.1 causing autosomal dominant retinitis pigmentosa (adRP). / Daiger, Stephen P.; Sullivan, Lori S.; Bowne, Sara J.; Koboldt, Daniel C.; Blanton, Susan H; Wheaton, Dianna K.; Avery, Cheryl E.; Cadena, Elizabeth D.; Koenekoop, Robert K.; Fulton, Robert S.; Wilson, Richard K.; Weinstock, George M.; Lewis, Richard A.; Birch, David G.

Advances in Experimental Medicine and Biology. Vol. 854 Springer New York LLC, 2016. p. 193-200 (Advances in Experimental Medicine and Biology; Vol. 854).

Research output: Chapter in Book/Report/Conference proceedingChapter

Daiger, SP, Sullivan, LS, Bowne, SJ, Koboldt, DC, Blanton, SH, Wheaton, DK, Avery, CE, Cadena, ED, Koenekoop, RK, Fulton, RS, Wilson, RK, Weinstock, GM, Lewis, RA & Birch, DG 2016, Identification of a novel gene on 10q22.1 causing autosomal dominant retinitis pigmentosa (adRP). in Advances in Experimental Medicine and Biology. vol. 854, Advances in Experimental Medicine and Biology, vol. 854, Springer New York LLC, pp. 193-200. https://doi.org/10.1007/978-3-319-17121-0_26
Daiger SP, Sullivan LS, Bowne SJ, Koboldt DC, Blanton SH, Wheaton DK et al. Identification of a novel gene on 10q22.1 causing autosomal dominant retinitis pigmentosa (adRP). In Advances in Experimental Medicine and Biology. Vol. 854. Springer New York LLC. 2016. p. 193-200. (Advances in Experimental Medicine and Biology). https://doi.org/10.1007/978-3-319-17121-0_26
Daiger, Stephen P. ; Sullivan, Lori S. ; Bowne, Sara J. ; Koboldt, Daniel C. ; Blanton, Susan H ; Wheaton, Dianna K. ; Avery, Cheryl E. ; Cadena, Elizabeth D. ; Koenekoop, Robert K. ; Fulton, Robert S. ; Wilson, Richard K. ; Weinstock, George M. ; Lewis, Richard A. ; Birch, David G. / Identification of a novel gene on 10q22.1 causing autosomal dominant retinitis pigmentosa (adRP). Advances in Experimental Medicine and Biology. Vol. 854 Springer New York LLC, 2016. pp. 193-200 (Advances in Experimental Medicine and Biology).
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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 sixgeneration 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 widelyexpressed 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.",
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AU - Blanton, Susan H

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AB - 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 sixgeneration 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 widelyexpressed 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.

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