Human Molecular Genetics, Vol 7, 1901-1906, Copyright © 1998 by Oxford University Press
G De Michele, F Cavalcanti, C Criscuolo, L Pianese, A Monticelli, A Filla and S Cocozza
Friedreich's ataxia is the first known autosomal recessive disease caused
by an unstable trinucleotide expansion mutation. The most frequent mutation
is expansion of a GAA repeat in the first intron of gene X25. We studied
transmission of the expanded GAA repeat in 37 Friedreich's ataxia pedigrees
and analysed blood and sperm alleles in eight patients. We showed
intergenerational instability in 84% of the alleles with an overall excess
of contractions. Both contractions and expansions of the GAA repeat
occurred in maternal transmission with a stronger tendency to expand for
smaller repeats and to contract for longer repeats. Paternally transmitted
alleles contracted only. Parental age and the intergenerational change in
expansion size were directly correlated in maternal transmission and
inversely in paternal transmission. The size of the GAA expansion was
slightly lower in patients than heterozygous carriers. Sperm analysis
confirmed the tendency to contract of paternal alleles, which was more
marked with ageing. The degree of contraction of the GAA repeat in sperm
was much higher than that found in intergenerational transmission and was
directly related to the repeat size. A blood expanded allele reverted to
normal size in the sperm of one patient. This study suggests the existence
of different mutational mechanisms in Friedreich's ataxia alleles, which
occur both pre- and post-zygotically.
ARTICLES
Parental gender, age at birth and expansion length influence GAA repeat intergenerational instability in the X25 gene: pedigree studies and analysis of sperm from patients with Friedreich's ataxia
Department of Neurological Sciences and Department of Molecular and Cellular Biology and Pathology and CEOS, Federico II University, via Pansini 5, 80131 Naples, Italy.
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