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

Waite, Adrian James, Carlisle, Francesca, Chan, Yiumo Michael and Blake, Derek 2016. Myoclonus dystonia and muscular dystrophy: ɛ-sarcoglycan is part of the dystrophin-associated protein complex in brain. Movement Disorders 31 (11) , pp. 1694-1703. 10.1002/mds.26738

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Abstract

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 International Parkinson and Movement Disorder Society.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: DYT11; dystonia; sarcoglycan
Publisher: Wiley
ISSN: 0885-3185
Funders: MRC
Date of First Compliant Deposit: 24 August 2016
Date of Acceptance: 27 June 2016
Last Modified: 04 Jun 2017 09:21
URI: http://orca-mwe.cf.ac.uk/id/eprint/94007

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