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© 1995 Oxford University Press

OTHER

Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population

Y.Paul Goldberg, Cynthia T. McMurray1,2, Jutta Zeisier, Elisabeth Almqvist, David Sillence3, Flona Richards3, A.Marquis Gacy2, Janet Buchanan4, Hâkan Telenius and Michael Hayden*

Department of Medical Genetics University of British Columbia 416-2125 East Mall, Vancouver, BC V6T 1Z4, Canada 1Departments of Pharmacology Mayo Foundation, 200 First Street, SW, Rochester, MN 55905, USA 2Departments of Biochemistry and Molecular Biology Mayo Foundation, 200 First Street, SW, Rochester, MN 55905, USA 3Departments of Genetics, Royal Alexandra Hospital for Children Pyrmont Bridge Road, Camperdown, NSW 2050, Australia 4Departments of Molecular Genetics North York General Hospital, 4001 Leslie Street, North York, Ontario M2K 1E1, Canada

*To whom correspondence should be addressed

Received June 1, 1995; Revised July 17, 1995; Accepted July 17, 1995

We have directly compared intergenerational stability of intermediate alleles (IAs) derived from new muta tion families (IANM) for Huntington disease (HD) with IAs in the general population (IAGP) which occur in ~1 in 50 persons. Analysis of meiotic events in blood and sperm reveals that IANM are significantly more unstable than IAGP despite similar size. However, for both IANM and IAGP CAG changes were small and risks for inheriting an expansion into the HD affected range were low. Sequence analysis reveals that the CAG tract is generally interrupted by a penultimate CAA in IAGP IANM and alleles in the affected range. In one new mutation family, however, two A->G mutations result In a pure CAG tract which is associated with very marked instability. These mutations alter the predicted DNA hairpin structure with a predicted increase in the likelihood of large expansion, supporting the model that hairpin loop formation plays an important role in trinucleotide instability.


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