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Mutations in DPAGT1 Cause a Limb-Girdle Congenital Myasthenic Syndrome with Tubular Aggregates

Lookup NU author(s): Emeritus Professor Clarke Slater, Dr Timothy Walls

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Abstract

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission.


Publication metadata

Author(s): Belaya K, Finlayson S, Slater CR, Cossins J, Liu WW, Maxwell S, McGowan SJ, Maslau S, Twigg SRF, Walls TJ, Pascual SIP, Palace J, Beeson D

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2012

Volume: 91

Issue: 1

Pages: 193-201

Print publication date: 01/07/2012

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ajhg.2012.05.022

DOI: 10.1016/j.ajhg.2012.05.022


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Funding

Funder referenceFunder name
Medical Research Council, UK
Muscular Dystrophy Campaign
Myasthenia Gravis Association
090532/Z/09/ZWellcome Trust
G0900747 91070Medical Research Council

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