title: Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2).
abstract: 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.
authors.affiliation: UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Eliana Marisa
authors.initials: EM
authors.lastname: Ramos
authors.affiliation: UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.|IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Martins
authors.affiliation: UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Alonso
authors.affiliation: Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Emmel
authors.affiliation: Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Maria Luiza
authors.initials: ML
authors.lastname: Saraiva-Pereira
authors.affiliation: Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Laura Bannach
authors.initials: LB
authors.lastname: Jardim
authors.affiliation: UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.|Hospital São Sebastião, Feira, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho
authors.affiliation: UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.|ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.affiliation: UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Silveira
mesh_terms: D000483:Alleles; D000067528:Ataxins; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
chemical_list: D000067528:Ataxins; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine