Myoclonus dystonia and muscular dystrophy: ε-sarcoglycan is part of the dystrophin-associated protein complex in brain

BackgroundMyoclonus-dystonia is a neurogenic movement disorder caused by mutations in the gene encoding -sarcoglycan. By contrast, mutations in the -, -, -, and -sarcoglycan genes cause limb girdle muscular dystrophies. The sarcoglycans are part of the dystrophin-associated protein complex in muscle that is disrupted in several types of muscular dystrophy. Intriguingly, patients with myoclonus-dystonia have no muscle pathology; conversely, limb-girdle muscular dystrophy patients have not been reported to have dystonia-associated features. To gain further insight into the molecular mechanisms underlying these differences, we searched for evidence of a sarcoglycan complex in the brain. MethodsImmunoaffinity chromatography and mass spectrometry were used to purify ubiquitous and brain-specific -sarcoglycan directly from tissue. Cell models were used to determine the effect of mutations on the trafficking and assembly of the brain sarcoglycan complex. ResultsUbiquitous and brain-specific -sarcoglycan isoforms copurify with -, -, and -sarcoglycan, -dystroglycan, and dystrophin Dp71 from brain. Incorporation of a muscular dystrophy-associated -sarcoglycan mutant into the brain sarcoglycan complex impairs the formation of the -sarcoglycan core but fails to abrogate the association and membrane trafficking of - and -sarcoglycan. Conclusions-Sarcoglycan is part of the dystrophin-associated protein complex in brain. Partial preservation of - and -sarcoglycan in brain may explain the absence of myoclonus dystonia-like features in muscular dystrophy patients. (c) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.