Nature Genetics
5, 174 - 179 (1993)
doi:10.1038/ng1093-174
Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effectsY. Paul Goldberg1, Berry Kremer1, Susan E. Andrew1, Jane Theilmann1, Rona K. Graham1, Ferdinando Squitieri1, Håkan Telenius1, Shelin Adam1, Anaar Sajoo1, Elizabeth Starr1, Arvid Heiberg2, Gerhard Wolff3
& Michael R. Hayden1
1Department of Medical Genetics, University of British Columbia, 416−2125 East Mall Vancouver, British Columbia V6T 2C1, Canada
2Frambu Helsesenter, 1404 Siggerud, Norway
3Institut für Humangenetik und Anthropologie, Universität Freiburg, Breisacherstrasse 33, D-7800 Freiburg, Germany Correspondence should be addressed to M.R.H. Huntington's disease (HD) is associated with expansion of a CAG repeat in a novel gene. We have assessed 21 sporadic cases of HD to investigate sequential events underlying HD. We show the existence of an intermediate allele (IA) in parental alleles of 30−38 CAG repeats in the HD gene which is greater than usually seen in the general population but below the range seen in patients with HD. These IAs are meiotically unstable and in the sporadic cases, expand to the full mutation associated with the phenotype of HD. This expansion has been shown to occur only during transmission through the male germline and is associated with advanced paternal age. These findings suggest that new mutations for HD are more frequent than prior estimates and indicate a previously unrecognized risk of inheriting HD to siblings of sporadic cases of HD and their children.
REFERENCES
- Harper, P.S. Huntington's Disease (W.B. Saunders, London, 1991).
- Hayden, M.R. Huntington's Chorea (Springer-Vertag, New York, 1981).
- Vogel, F. & Motulsky, A. Human Genetics 2nd edn (Springer-Verlag, New York, 1986).
- Huntington Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on HD chromosomes. Cell 72, 971−983 (1983).
- Andrew, S.E. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington Disease. Nature Genet. 4, 398−403, (1993).
- Wolff, G. et al. New Mutation to Huntington's Disease. J. med. Genet. 26, 18−27 (1989).
- Barattser, M., Bum, J. & Fazzone, T.A. Huntington's chorea arising as a fresh mutation. J. med. Genet. 20, 459−460 (1983).
- Shaw, M. & Caro, A. The mutation rate to Huntington's chorea. J. Med. Genet. 19, 161−167 (1982).
- Chiu, E. & Brackenridge, C.J. A probable case of mutation in Huntington's disease. J. med. Genet. 13, 75−77 (1976).
- Stevens, D. & Parsonage, M. Mutation in Huntington's chorea. J. Neurol. Neurosurg. Psychiat. 32, 140−143 (1969).
- MacDonald, M.E. et al. The Huntington's disease candidate region exhibits many different haplotypes. Nature Genet. 1, 99−103 (1969).
- Andrew, S.E. et al. DNA analysis of distinct populations suggest multiple origins for the mutation causing Huntington Disease. Clin. Genet. 43, 286−294 (1993).
- Fu, Y-h. et al. Variation of the CCG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047−1058 (1991).
- Kremer, E.J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711−1714 (1991).
- Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science 255, 1253−1255 (1992).
- Fu, Y-H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256−1258 (1992).
- 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).
- Barcelo, J.M. et al. Intergenerational stability of the myotonic dystrophy protomutation. Hum. molec. Genet 6, 705−709,1993.
- Brook, J.D. Retreat of the triplet repeat? Nature Genet. 3, 279−281 (1993).
- Penrose, L.S. Parental age and mutation. Lancet II, 312 (1955).
- Penrose, L.S. Parental age in achondroplasia and mongolism. Am. J. hum. Genet. 9, 167−169 (1957).
- Murdoch, J., Walker, B.A. & McKusick, V.A. Parental age effects on the occurrence of new mutations for the Marfan syndrome. Ann. hum. Genet. 35, 331−336 (1972).
- Vogel, F. A probable sex difference in some mutation rates.Am. J. hum. Genet. 29, 312−319 (1977).
- Kunkel, L.M. et al. Analysis of human Y chromosome specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A. 74, 1245−1249 (1977).
- Goldberg, Y.P., Andrew, S.E., Clarke, L.A. & Hayden, M.R. A PCR method for accurate assessment of trinucleotide repeat expansion in Huntington Disease. Hum. molec. Genet 2, 635−636 (1993).
- Zar, J.H. (ed.) Biostatistical Analysis 2nd edn 370−371 (Prentice-Hall, New Jersey, (1984).
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