Nature Genetics
4, 393 - 397 (1993)
doi:10.1038/ng0893-393
Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's diseaseRussell G. Snell1, John C. MacMillan1, Jeremy P. Cheadle1, Iain Fenton1, Lazarus P. Lazarou1, Peter Davies1, Marcy E. MacDonald2, James F. Gusella2, Peter S. Harper1
& Duncan J. Shaw1
1Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK
2Molecular Neurogenetics Unit Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA Correspondence should be addressed to P.S.H. The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30−70 repeats in affected individuals and 9−34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex−specific modifying effect.
REFERENCES
- Harper, P.S. Huntington's disease. (W.B. Saunders, London, 1991).
- The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971−983 (1993). | PubMed | ISI |
- Brook, J.D. et al. Molecular basis of Myotonic Dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 68, 799−808 (1992). | Article | PubMed | ISI | ChemPort |
- Verkerk, A.J.M.H. et al. Identification of a gene (FMR-1) containing a CCG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905−914 (1991). | PubMed | ISI | ChemPort |
- LaSpada, A.R. et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular dystrophy. Nature 352, 77−79 (1991). | Article | PubMed | ISI | ChemPort |
- Orr, H. et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221−226 (1993). | Article | PubMed | ISI | ChemPort |
- Krawczak, M. et al. Covariate-dependent age-at-onset distributions for Huntington Disease. Am. J. hum. Genet. 49, 735−745 (1991). | PubMed | ISI | ChemPort |
- Went, L.N., Vegter-van der Vlis, M., Bruyn, G.W. & Volkers, W.S. Huntington's chorea in the Netherlands: the problem of genetic heterogeneity. Ann. hum. Genet. 47, 205−214 (1983). | PubMed | ISI |
- Farrer, L.A. and Conneally, P.M. A genetic model for age at onset in Huntington disease. Am. J. hum. Genet. 37, 350−357 (1985). | PubMed | ISI | ChemPort |
- Farrer, L.A., Conneally, P.M. and Yu, P. The natural history of Huntington's disease: possible role of aging genes. Am. J. med. Genet. 18, 115−123 (1984). | PubMed | ISI | ChemPort |
- Merrit, A.D., Conneally, P.M., Rahman, N.F.andDrew, A.L. Juvenile Huntington's chorea. In Progress in Neurogenetics (eds A. Barbeau & J.R. Brunette) 645−650 (Excerpta Medica Foundation, Amsterdam, 1969).
- Myers, R.H., Goldman, D. & Bird, E.D. Maternal transmission in Huntington's disease. Lancet i, 208−210 (1983). | Article |
- Went, L.N., Vegter-van der Vlis, M. & Bruyn, G.W. Parental transmission in Huntington's disease. Lancet i, 1100−1102 (1984). | Article |
- Ridley, R.M., Frith, C.D., Farrer, L.A. & Conneally, P.M. Patterns of inheritance of the symptoms of Huntington's disease suggestive of an effect of genomic imprinting. J. med. Genet. 28, 224−231 (1991). | PubMed | ISI | ChemPort |
- Harley, H.G. et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355, 545−546 (1992). | Article | PubMed | ISI | ChemPort |
- Buxton, J. et al. Detection of an unstable fragment of DNA specific to individuals with Myotonic dystrophy. Nature 355, 547−548 (1992). | Article | PubMed | ISI | ChemPort |
- Harper, P.S., Harley, H.G., Reardon, W. & Shaw, D.J. Anticipation in Myotonic Dystrophy: New light on an old problem. Am. J. hum. Genet. 51, 10−16 (1992). | PubMed | ISI | ChemPort |
- Newcombe, R.G., Walker, D.A. & Harper, P.S. Factors influencing age of onset and duration of survival in Huntington's chorea. Ann. hum. Genet. 45, 387−396 (1981). | PubMed | ISI | ChemPort |
- Farrer, L.A. et al. The normal HD allele, or a closely linked gene, influences age at onset of Huntington Disease. Am. J. hum. Genet. (in the press).
- Snell, R.G. et al. Linkage disequilibrium in the Huntington's disease: an improved localization for the gene. J. med. Genet. 26, 273−275 (1989).
- Theilmann, J. et al. Non-random association between alleles detected at D4S95 and D4S98 and the Huntington's disease gene. J. med. Genet. 26, 676−681 (1989). | PubMed | ISI | ChemPort |
- MacDonald, M.E. et al. Complex patterns of linkage disequilibrium in the Huntington disease region. Am. J. hum. Genet. 49, 723−734 (1991). | PubMed | ISI | ChemPort |
- Fenton, I. & Sandkuijl, L.A. Megabase/PKD: A genetic database for polycystic kidney disease. Second International Workshop on PKD 70−74 (1992).
|
