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Human Molecular Genetics, 2000, Vol. 9, No. 13 1957-1966
© 2000 Oxford University Press

CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation

Claudia Gaspar+, Merhdad Jannatipour+, Patrick Dion, Janet Laganière, Jorge Sequeiros1, Bernard Brais§ and Guy A. Rouleau

Centre for Research in Neurosciences, McGill University, and the Montreal General Hospital, 1650 Cedar Avenue, Montréal, Québec H3G 1A4, Canada and 1Laboratório Genética Médica, ICBAS and UnIGENe, IBMC, Universidade do Porto, Porto, Portugal

Machado–Joseph disease (MJD) is one of several disorders caused by the expansion of a coding CAG repeat (exp-CAG). The presence of intranuclear inclusions (INIs) in patients and cellular models of exp-CAG-associated diseases has lead to a nuclear toxicity model. Similar INIs are found in oculopharyngeal muscular dystrophy, which is caused by a short expansion of an alanine-encoding GCG repeat. Here we propose that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins. We hypothesize that these alanine polymers deposit in cells forming INIs and may contribute to nuclear toxicity. We show evidence that supports our hypothesis in lymphoblast cells from MJD patients, as well as in pontine neurons of MJD brain and in in vitro cell culture models of the disease. We also provide evidence that alanine polymers alone are harmful to cells and predict that a similar pathogenic mechanism may occur in the other CAG repeat disorders.

+ These authors contributed equally to this work

§ Present address: Centre de recherche du CHUM, Campus Notre-Dame, Université de Montréal, 1560 rue Sherbrooke est, Montréal, Québec H2L 4M1, Canada

To whom correspondence should be addressed. Tel: +1 514 934 8094; Fax: 514 934 8265; Email: mi32@musica.mcgill.ca


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