Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2).
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.
Ramos
Eliana Marisa
EM
UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
Martins
Sandra
S
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.
Alonso
Isabel
I
UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
Emmel
Vanessa E
VE
Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Saraiva-Pereira
Maria Luiza
ML
Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Jardim
Laura Bannach
LB
Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Coutinho
Paula
P
UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.|Hospital São Sebastião, Feira, Portugal.
Sequeiros
Jorge
J
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.
Silveira
Isabel
I
UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
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
D000067528:Ataxins; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine