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.
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Article Synopsis
- A CGG repeat expansion in the 5' UTR of the GIPC1 gene is linked to oculopharyngodistal myopathy (OPDM), a hereditary muscle disorder causing symptoms like eyelid drooping and muscle weakness.
- This mutation has also been associated with Parkinson's disease, although without myopathy symptoms in those cases.
- In two unrelated cases, patients with myopathic symptoms later developed parkinsonism, indicating that GIPC1-related repeat expansions may lead to various neuromuscular issues, highlighting the need to recognize central nervous system symptoms in OPDM2.
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