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.
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References
Berger W, Kloeckener-Gruissem B, Neidhardt J (2010) The molecular basis of human retinal and vitreoretinal diseases. Prog Ret Eye Res 29:335–375
Bowne SJ, Humphries MM, Sullivan LS et al (2011) A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Euro J Hum Genet 19:1074–1081
Churchill JD, Bowne SJ, Sullivan LS et al (2013) Mutations in the X-linked retinitis pigmentosa genes RPGR and RP2 found in 8.5 % of families with a provisional diagnosis of autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 54:1411–1416
Daiger SP, Bowne SJ, Sullivan LS (2007) Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol 125:151–158
Daiger SP, Bowne SJ, Sullivan LS (2014a) Genes and mutations causing autosomal dominant retinitis pigmentosa. Cold Spring Harb Perspect Med. pii: a017129. doi: 10.1101/cshperspect.a017129. [Epub ahead of print]
Daiger SP, Bowne SJ, Sullivan LS et al (2014b) Application of next-generation sequencing to identify genes and mutations causing autosomal dominant retinitis pigmentosa (adRP). Adv Exp Med Biol 801:123–129
Haim M (2002) Epidemiology of retinitis pigmentosa in Denmark. Acta Ophthalmol Scand Suppl 233:1–34
Koboldt DC, Larson DE, Sullivan LS et al (2014) Exome-based mapping and variant prioritization for inherited Mendelian disorders. Am J Hum Genet 94:373–384
RetNet (2014) The Retinal Information Network, http://www.sph.uth.tmc.edu/RetNet/. In: Stephen P. Daiger, PhD, Administrator, The University of Texas Health Science Center at Houston
Sohocki MM, Daiger SP, Bowne SJ et al (2001) Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies. Hum Mutat 17:42–51
Sullivan LS, Bowne SJ, Birch DG et al (2006) Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci 47:3052–3064
Sullivan LS, Koboldt DC, Bowne SJ, Lang S, Blanton SH, Cadena E, Avery CE, Lewis RA, Webb-Jones K, Wheaton DH, Birch DG, Coussa R, Ren H, Lopez I, Chakarova C, Koenekoop RK, Garcia CA, Fulton RS, Wilson RK, Weinstock GM, Daiger SP (2014). A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa. Invest Ophthalmol Vis Sci 55:7147–7158.
Wang F, Wang H, Tuan HF et al (2013) Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet 133:331–345
Wright AF, Chakarova CF, Abd El-Aziz MM et al (2010) Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11:273–284
Acknowledgements
We dedicate this report to the memory of Dr. Mary Kay Pelias who worked closely with the Louisiana families throughout her career. This work was supported by NIH grant EY007142, by grant HG003079 from the NHGRI, by a Wynn-Gund TRAP Award, and by the Foundation Fighting Blindness.
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Daiger, S. et al. (2016). Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP). In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_26
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DOI: https://doi.org/10.1007/978-3-319-17121-0_26
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