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

Abstract

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.