Journal Article

CAG tract of <i>MJD-1</i> may be prone to frameshifts causing polyalanine accumulation

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

in Human Molecular Genetics

Volume 9, issue 13, pages 1957-1966
Published in print August 2000 | ISSN: 0964-6906
Published online August 2000 | e-ISSN: 1460-2083 | DOI:
CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation

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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.

Journal Article.  5236 words.  Illustrated.

Subjects: Genetics and Genomics

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