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Human Molecular Genetics, 2000, Vol. 9, No. 12 1753-1758
© 2000 Oxford University Press

CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2)

Sean Hayes1,2, Gustavo Turecki2,3, Katéri Brisebois2, Iscia Lopes-Cendes4, Claudia Gaspar2,5, Olaf Riess5, Laura P.W. Ranum7, Stefan-M. Pulst8 and Guy A. Rouleau2,+

1Department of Biology, 2Centre for Research in Neurosciences and 3Douglas Hospital Research Institute, McGill University, Montreal, Quebec H3G 1A4, Canada, 4Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP 13081-970, Brazil, 5Laboratorio Genética Médica, ICBAS and UnIGENe, IBMC Iniversidade do Porto, Porto, Portugal, Department of Molecular Human Genetics, Ruhr University, Bochum D-44780, Germany, 7Departments of Neurology and Genetics, Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA and 8Division of Neurology and Rose Moss Laboratory for Parkinson’s and Neurodegenerative Disorders, Burns and Allen Research Institute, University of California, Los Angeles, CA 90048, USA

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by the expansion of a polymorphic (CAG)n tract, which is translated into an expanded polyglutamine tract in the ataxin-2 protein. Although repeat length and age at disease onset are inversely related, ~50% of the age at onset variance in SCA2 remains unexplained. Other familial factors have been proposed to account for at least part of this remaining variance in the polyglutamine dis­orders. The ability of polyglutamine tracts to interact with each other, as well as the presence of intra­nuclear inclusions in other polyglutamine disorders, led us to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, we used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. One locus, RAI1, contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the SCA2 expanded repeat. This locus was further studied in SCA3/Machado–Joseph disease (MJD), but did not have an effect on SCA3/MJD age at onset. This result implicates RAI1 as a possible contributor to SCA2 neurodegeneration and raises the possibility that other CAG-containing proteins may play a role in the pathogenesis of other polyglutamine disorders.

+ To whom correspondence should be addressed at: L7-224 Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada. Tel: +1 514 934 8094; Fax: +1 514 934 8265; Email: mi32@musica.mcgill.ca


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