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Neuromuscul Disord. 2017 Nov;27(11):1043-1046. doi: 10.1016/j.nmd.2017.07.006. Epub 2017 Jul 17.

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

Author information

1
Neuromuscular Reference Centre, University Hospital St-Luc, University of Louvain, Brussels, Belgium. Electronic address: peter.vandenbergh@uclouvain.be.
2
Neuromuscular Reference Centre, University Hospital St-Luc, University of Louvain, Brussels, Belgium; Centre for Human Genetics, University Hospital St-Luc, University of Louvain, Brussels, Belgium.
3
Neuromuscular Reference Centre, University Hospital St-Luc, University of Louvain, Brussels, Belgium.
4
Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands; Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands.
5
Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands.
6
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
7
The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon-Tyne, United Kingdom.

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.

KEYWORDS:

Alpha-dystroglycan; DPM3; Dolichol-P-mannose synthase; Limb girdle muscular dystrophy

PMID:
28803818
DOI:
10.1016/j.nmd.2017.07.006
[Indexed for MEDLINE]

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