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Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2)
Author(s) -
Ramos Eliana Marisa,
Martins Sandra,
Alonso Isabel,
Emmel Vanessa E.,
SaraivaPereira Maria Luiza,
Jardim Laura Bannach,
Coutinho Paula,
Sequeiros Jorge,
Silveira Isabel
Publication year - 2010
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.31013
Subject(s) - spinocerebellar ataxia , allele , genetics , biology , haplotype , ataxia , trinucleotide repeat expansion , mutation , disease , medicine , gene , pathology , neuroscience
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.