Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset

Abstract

Huntington's disease (HD) has recently been found to be caused by expansion of a trinucleotide (CAG) repeat within the putative coding region of a gene with an unknown function. We report here an analysis of HD mutation and the characteristics of its transmission in 36 HD families. CAG repeats on HD chromosomes were unstable when transmitted from parent to offspring. Instability appeared more frequent and stronger upon transmission from a male than from a female, with a clear tendency towards increased size. We have also found a significant inverse correlation (p = 0.0001) between the age of onset and the CAG repeat length. The observed scatter would, however, not allow an accurate individual prediction of age of onset. Three juvenile onset cases analysed had an HD mutation of paternal origin. In at least two of these cases a large expansion of the HD allele upon paternal transmission may explain the major anticipation observed. Our results suggest that several features of the expansion mutation in HD are similar to those previously observed for mutations of similar size in spinobulbar muscular atrophy and in myotonic dystrophy, and to those observed more recently in spinocerebellar ataxia type 1 and in dentatorubropallidoluysian atrophy, four diseases also caused by expansion of CAG repeats.