title: Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus.
abstract: The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neurodegenerative disorders, has been mapped to chromosome 14q32.1. ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region. We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropathological findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD. Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease. Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation. Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats.
authors.affiliation: INSERM U289, Hôpital de la Salpêtrière, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Cancel
authors.forename: N
authors.initials: N
authors.lastname: Abbas
authors.forename: G
authors.initials: G
authors.lastname: Stevanin
authors.forename: A
authors.initials: A
authors.lastname: Dürr
authors.forename: H
authors.initials: H
authors.lastname: Chneiweiss
authors.forename: C
authors.initials: C
authors.lastname: Néri
authors.forename: C
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: C
authors.initials: C
authors.lastname: Penet
authors.forename: H M
authors.initials: HM
authors.lastname: Cann
authors.forename: Y
authors.initials: Y
authors.lastname: Agid
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002648:Child; D018740:Genetic Heterogeneity; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics*; D008875:Middle Aged; D009030:Mosaicism; D010641:Phenotype; D012091:Repetitive Sequences, Nucleic Acid; D013132:Spinocerebellar Degenerations / Q000235:genetics*