RESUMO
Spinocerebellar ataxia type 10 (SCA10; MIM 603516; refs 1,2) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. The gene SCA10 maps to a 3.8-cM interval on human chromosome 22q13-qter (refs 1,2). Because several other SCA subtypes show trinucleotide repeat expansions, we examined microsatellites in this region. We found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of SCA10 in all patients in five Mexican SCA10 families. There was an inverse correlation between the expansion size, up to 22.5 kb larger than the normal allele, and the age of onset (r2=0.34, P=0.018). Analysis of 562 chromosomes from unaffected individuals of various ethnic origins (including 242 chromosomes from Mexican persons) showed a range of 10 to 22 ATTCT repeats with no evidence of expansions. Our data indicate that the new SCA10 intronic ATTCT pentanucleotide repeat in SCA10 patients is unstable and represents the largest microsatellite expansion found so far in the human genome.
Assuntos
Cromossomos Humanos Par 22 , DNA/genética , Sequências Repetitivas de Ácido Nucleico , Ataxias Espinocerebelares/genética , Animais , Povo Asiático/genética , Encéfalo/metabolismo , Encéfalo/patologia , Mapeamento Cromossômico , DNA/sangue , DNA/química , Epilepsia/genética , Epilepsia/patologia , Feminino , Humanos , Masculino , Americanos Mexicanos/genética , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Linhagem , Polimorfismo Genético , Ataxias Espinocerebelares/patologia , Estados Unidos , População Branca/genéticaRESUMO
We investigated a family with a new type of autosomal dominant cerebellar ataxia (ADCA) in which pure cerebellar ataxia is often accompanied with epilepsy. No CAG repeat expansions were detected at the spinocerebellar ataxia (SCA) type 1, 2, 3, 6, or 7 locus, and SCAs 4 and 5 were excluded by linkage analysis. We found linkage between the disease locus and D22S274 (Zmax = 3.86 at theta = 0.00) and two other makers in 22q13-qter. Haplotype analysis of the crossover events and the multipoint linkage mapping localized the disease locus to an 8.8-cM region between D22S1177 and D22S1160.