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

BACKGROUND: Myoclonus‐dystonia is a neurogenic movement disorder caused by mutations in the gene encoding ɛ‐sarcoglycan. By contrast, mutations in the α‐, β‐, γ‐, and δ‐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. METHODS: Immunoaffinity chromatography and mass spectrometry were used to purify ubiquitous and brain‐specific ɛ‐sarcoglycan directly from tissue. Cell models were used to determine the effect of mutations on the trafficking and assembly of the brain sarcoglycan complex. RESULTS: Ubiquitous and brain‐specific ɛ‐sarcoglycan isoforms copurify with β‐, δ‐, and ζ‐sarcoglycan, β‐dystroglycan, and dystrophin Dp71 from brain. Incorporation of a muscular dystrophy‐associated β‐sarcoglycan mutant into the brain sarcoglycan complex impairs the formation of the βδ‐sarcoglycan core but fails to abrogate the association and membrane trafficking of ɛ‐ and ζ‐sarcoglycan. CONCLUSIONS: ɛ‐Sarcoglycan is part of the dystrophin‐associated protein complex in brain. Partial preservation of ɛ‐ and ζ‐sarcoglycan in brain may explain the absence of myoclonus dystonia‐like features in muscular dystrophy patients. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.