A gain-of-glycosylation mutation associated with myoclonus-dystonia syndrome affects trafficking and processing of mouse ε-sarcoglycan in the late secretory pathway

Waite, Adrian James, De Rosa, Maria Cristina, Brancaccio, Andrea and Blake, Derek J. ORCID: https://orcid.org/0000-0002-5005-4731 2011. A gain-of-glycosylation mutation associated with myoclonus-dystonia syndrome affects trafficking and processing of mouse ε-sarcoglycan in the late secretory pathway. Human Mutation 32 (11) , pp. 1246-1258. 10.1002/humu.21561

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Abstract

Missense mutations in the SGCE gene encoding ε-sarcoglycan account for approximately 15% of SGCE-positive cases of myoclonus-dystonia syndrome (MDS) in humans. In this study, we show that while the majority of MDS-associated missense mutants modeled with a murine ε-sarcoglycan cDNA are substrates for endoplasmic reticulum-associated degradation, one mutant, M68T (analogous to human c.275T>C, p.M92T), located in the Ig-like domain of ε-sarcoglycan, results in a gain-of-glycosylation mutation producing a protein that is targeted to the plasma membrane, albeit at reduced levels compared to wild-type ε-sarcoglycan. Removal of the ectopic N-linked glycan failed to restore efficient plasma membrane targeting of M68T demonstrating that the substitution rather than the glycan was responsible for the trafficking defect of this mutant. M68T also colocalized with CD63-positive vesicles in the endosomal–lysosomal system and was found to be more susceptible to lysosomal proteolysis than wild-type ε-sarcoglycan. Finally, we demonstrate impaired ectodomain shedding of M68T, a process that occurs physiologically for ε-sarcoglycan resulting in the lysosomal trafficking of the intracellular C-terminal domain of the protein. Our findings show that functional analysis of rare missense mutations can provide a mechanistic insight into the pathogenesis of MDS and the physiological role of ε-sarcoglycan.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords:	dystonia; Sarcoglycan; Glycosylation; Mutant; Ectodomain cleavage; Lysosome
Publisher:	Wiley-Blackwell
ISSN:	1059-7794
Last Modified:	19 Oct 2022 09:59
URI:	https://orca.cardiff.ac.uk/id/eprint/22850

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