Progress in understanding the pathogenesis of oculopharyngeal muscular dystrophy.
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 PABPN I function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPNI 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.
Fan
Xueping
X
Center for Research in Neuroscience, McGill University, and the McGill University Health Center, Montreal, Quebec, Canada.
Rouleau
Guy A
GA
D000328:Adult; D000818:Animals; D016923:Cell Death; D002467:Cell Nucleus / Q000473:pathology; D018450:Disease Progression; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D056918:Nuclear Receptor Coactivators; D010455:Peptides / Q000502:physiology; D014157:Transcription Factors
D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009687:Nuclear Proteins; D056918:Nuclear Receptor Coactivators; D010455:Peptides; C111791:SNW1 protein, human; D014157:Transcription Factors; C019529:polyalanine