De novo expansion of intermediate alleles in spinocerebellar ataxia 7.
Human Molecular Genetics. 1998-10-01; 7(11): 1809-1813
DOI: 10.1093/hmg/7.11.1809
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1. Hum Mol Genet. 1998 Oct;7(11):1809-13.
De novo expansion of intermediate alleles in spinocerebellar ataxia 7.
Stevanin G(1), Giunti P, Belal GD, Dürr A, Ruberg M, Wood N, Brice A.
Author information:
(1)INSERM U289, Hôpital de la Salpêtrière, 75013 Paris, France.
Spinocerebellar ataxia 7 (SCA7) is the eighth neurodegenerative disorder caused
by a translated CAG repeat expansion. Normal SCA7 alleles carry from four to 35
CAG repeats, whereas pathological alleles carry from 37 to approximately 200.
Intermediate alleles (IAs), with 28-35 repeats in the SCA7 gene are exceedingly
rare in the general population and are not associated with the SCA7 phenotype,
although they have been found among relatives of four SCA7 families. In two of
these families, IAs bearing 35 and 28 CAG repeats gave rise, during paternal
transmission, to SCA7 expansions of 57 and 47 repeats, respectively, that were
confirmed by haplotype reconstructions in one case and by inference in the other.
Furthermore, the four haplotypes segregating with IAs were identical to the
expanded alleles in each kindred, but differed among the families, indicating
multiple origins of the SCA7 mutation in these families with different
geographical origins. Our results provide the first evidence of de novo SCA7
expansions from IAs that are not associated with the phenotype but can expand to
the pathological range during some paternal transmissions. IAs that segregate in
unaffected branches of the pedigrees might, therefore, constitute a reservoir for
future de novo mutations that occur in a recurrent but random manner. This would
explain the persistence of the disease in spite of the great anticipation
(approximately 20 years/generation) characteristic of SCA7. So far, de novo
expansions among the disorders caused by polyglutamine repeats have only been
demonstrated in Huntington’s disease.
DOI: 10.1093/hmg/7.11.1809
PMID: 9736784 [Indexed for MEDLINE]