A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy.

Abstract

Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy.

• Authors: P Y K Van den Bergh, Y Sznajer, V Van Parys, W van Tol, R A Wevers, D J Lefeber, L Xu, M Lek, D G MacArthur, K Johnson, L Phillips, A Töpf, V Straub
• Journal: Neuromuscular disorders : NMD (Neuromuscul Disord) Vol. 27 Issue 11 Pg. 1043-1046 (Nov 2017) ISSN: 1873-2364 [Electronic] England
• PMID: 28803818 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Membrane Proteins
• Dystroglycans
• Mannosyltransferases
• DPM3 protein, human

Topics

• Dystroglycans (metabolism)
• Female
• Homozygote
• Humans
• Mannosyltransferases (genetics)
• Membrane Proteins (genetics)
• Middle Aged
• Muscle, Skeletal (diagnostic imaging, pathology)
• Muscular Dystrophies, Limb-Girdle (diagnostic imaging, genetics, metabolism, pathology)
• Mutation
• Phenotype