Dataset Information

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

ABSTRACT:

Background

Myoclonus-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.

Methods

Immunoaffinity 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.

Results

Ubiquitous 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. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Waite AJ

PROVIDER: S-EPMC5129563 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Waite Adrian J AJ Carlisle Francesca A FA Chan Yiumo Michael YM Blake Derek J DJ

Movement disorders : official journal of the Movement Disorder Society 20160818 11

<h4>Background</h4>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 ha ...[more]

PMID: 27535350

Similar Datasets

Project description:Limb-girdle muscular dystrophy type 2D/R3 (LGMD2D/R3) is a progressive muscular dystrophy that manifests with muscle weakness, respiratory abnormalities, and in rare cases cardiomyopathy. LGMD2D/R3 is caused by mutations in the SGCA gene resulting in loss of protein and concomitant loss of some or all components of the dystrophin-associated glycoprotein complex. The sgca-null (sgca-/-) mouse recapitulates the clinical phenotype of patients with LGMD2D/R3, including dystrophic features such as muscle necrosis and fibrosis, elevated serum creatine kinase (CK), and reduction in the generation of absolute muscle force and locomotor activity. Thus, sgca-/- mice provide a relevant model to test the safety and efficacy of gene transfer. We designed a self-complementary AAVrh74 vector containing a codon-optimized full-length human SGCA (hSGCA) transgene driven by a muscle-specific promoter, shortened muscle creatine kinase (tMCK). In this report, we test the efficacy and safety of scAAVrh74.tMCK.hSGCA in sgca-/- mice using a dose-escalation design to evaluate a single systemic injection of 1.0 × 1012, 3.0 × 1012, and 6.0 × 1012 vg total dose compared with vehicle-treatment and wild-type mice. In sgca-/- mice, treatment with scAAVrh74.tMCK.hSGCA resulted in robust expression of α-sarcoglycan protein at the sarcolemma membrane in skeletal muscle at all doses tested. In addition, scAAVrh74.tMCK.hSGCA was effective in improving the histopathology of limb and diaphragm muscle of sgca-/- mice, as indicated by reductions in fibrosis, central nucleation, and normalization of myofiber size. These molecular changes were concomitant with significant increases in specific force generation in the diaphragm and tibialis anterior muscle, protection against eccentric force loss, and reduction in serum CK. Locomotor activity was improved at all doses of vector-treated compared with vehicle-treated sgca-/- mice. Lastly, vector toxicity was not detected in a serum chemistry panel and by gross necropsy. Collectively, these findings provide support for a systemic delivery of scAAVrh74.tMCK.hSGCA in a clinical setting for the treatment of LGMD2D/R3.