Produção Nacional
Revisado por pares
Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2)
2009; Wiley; Volume: 153B; Issue: 2 Linguagem: Inglês
10.1002/ajmg.b.31013
ISSN1552-485X
AutoresEliana Marisa Ramos, Sandra Martins, Isabel Alonso, Vanessa E Emmel, Maria Luiza Saraiva Pereira, Laura Bannach Jardim, Paula Coutinho, Jorge Sequeiros, Isabel Silveira,
Tópico(s)Muscle Physiology and Disorders
ResumoAbstract The spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by gait and limb ataxia. This disease is caused by the expansion of a (CAG) n located in the ATXN2 , that encodes a polyglutamine tract of more than 34 repeats. Lately, alleles with 32–33 CAGs have been associated to late‐onset disease cases. Repeat interruptions by CAA triplets are common in normal alleles, while expanded alleles usually contain a pure repeat tract. To investigate the mutational origin and the instability associated to the ATXN2 repeat, we performed an extensive haplotype study and sequencing of the CAG/CAA repeat, in a cohort of families of different geographic origins and phenotypes. Our results showed (1) CAA interruptions also in expanded ATXN2 alleles; (2) that pathological CAA interrupted alleles shared an ancestral haplotype with pure expanded alleles; and (3) higher genetic diversity in European SCA2 families, suggesting an older European ancestry of SCA2. In conclusion, we found instability towards expansion in interrupted ATXN2 alleles and a shared ancestral ATXN2 haplotype for pure and interrupted expanded alleles; this finding has strong implications in mutation diagnosis and counseling. Our results indicate that interrupted alleles, below the pathological threshold, may be a reservoir of mutable alleles, prone to expansion in subsequent generations, leading to full disease mutation. © 2009 Wiley‐Liss, Inc.
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