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Progress in Understanding the Pathogenesis of Oculopharyngeal Muscular Dystrophy

Published online by Cambridge University Press:  02 December 2014

Xueping Fan  and
Guy A. Rouleau
Xueping Fan
Affiliation:
Center for Research in Neuroscience, McGill University, and the McGill University Health Center, Montreal, Quebec, Canada
Guy A. Rouleau
Affiliation:
Center for Research in Neuroscience, McGill University, and the McGill University Health Center, Montreal, Quebec, Canada
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Abstract

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Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness. The autosomal dominant form of this disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. These mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1) induces the formation of muscle intranuclear inclusions that are thought to be the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and PABPN1 function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPN1 in the formation and toxicity of OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis that accounts for these observations.

Résumé:

RÉSUMÉ:

La dystrophie musculaire oculopharyngée (DMOP) est une maladie de l’âge adulte caractérisée par une chute progressive de la paupière supérieure (ptose), des difficultés de déglutition (dysphagie) et une faiblesse musculaire proximale. La forme autosomique dominante de la maladie est causée par une expansion de répétitions GCG de 6 à 8-13 répétitions dans le gène PABPN1. Ces mutations provoquent l’expansion d’une séquence de polyalanine de 10 à 12-17 alanines dans le domaine n-terminal de PABPN1. Le gène PABPN1 muté (mPABPN1) entraîne la formation d’inclusions intranucléaires musculaires qui sont considérées comme les stigmates de cette maladie. Dans cette revue, nous discutons: 1) de la génétique de la DMOP et des études de fonction du gène PABPN1; 2) des maladies causées par une expansion polyalanine et de la toxicité cellulaire de la polyalanine; 3) de la toxicité des inclusions intranucléaires dues à mPABPN1; 4) du rôle de l’oligomérisation de mPABPN1 dans la formation et la toxicité des inclusions intranucléaires de la DMOP et 5) du recrutement de composantes subcellulaires aux inclusions de la DMOP. Nous présentons un mécanisme moléculaire de la pathogenèse de la DMOP qui expliquerait toutes ces observations.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 30 , Issue 1 , February 2003 , pp. 8 - 14
Copyright
Copyright © The Canadian Journal of Neurological 2003

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