title: Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease.
abstract: Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicism, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.
authors.affiliation: Centre for Research in Neuroscience, McGill University, Montreal General Hospital Research Institute, Quebec, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Lopes-Cendes
authors.forename: P
authors.initials: P
authors.lastname: Maciel
authors.forename: S
authors.initials: S
authors.lastname: Kish
authors.forename: C
authors.initials: C
authors.lastname: Gaspar
authors.forename: Y
authors.initials: Y
authors.lastname: Robitaille
authors.forename: H B
authors.initials: HB
authors.lastname: Clark
authors.forename: A H
authors.initials: AH
authors.lastname: Koeppen
authors.forename: M
authors.initials: M
authors.lastname: Nance
authors.forename: L
authors.initials: L
authors.lastname: Schut
authors.forename: I
authors.initials: I
authors.lastname: Silveira
authors.forename: P
authors.initials: P
authors.lastname: Coutinho
authors.forename: J
authors.initials: J
authors.lastname: Sequeiros
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D017668:Age of Onset; D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D001933:Brain Stem / Q000473:pathology; D016923:Cell Death; D002531:Cerebellum / Q000002:abnormalities / Q000473:pathology; D006801:Humans; D017827:Machado-Joseph Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009030:Mosaicism / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology; D013132:Spinocerebellar Degenerations / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018911:Trinucleotide Repeats / Q000235:genetics