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A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy
P Y K Van den Bergh1, Y Sznajer2, V Van Parys1
1Neuromuscular Reference Centre, University Hospital St-Luc, University of Louvain, Brussels, Belgium.
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.
Insights
Mutations in DPM3, a gene involved in O-linked glycosylation, can cause limb girdle muscular dystrophy. This study identifies a novel DPM3 mutation leading to mild, isolated muscle weakness without heart issues.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- O-linked glycosylation defects in alpha-dystroglycan are linked to various muscular dystrophies.
- These defects range from severe congenital forms with developmental abnormalities to milder limb girdle muscular dystrophies.
Observation:
- A 42-year-old female presented with isolated pelvic girdle muscle weakness and wasting.
- Exome sequencing revealed a homozygous mutation (c.131T>G, p.Leu44Pro) in the DPM3 gene.
Findings:
- The identified DPM3 mutation reduced dolichol-P-mannose (DPM) synthase activity by 50%.
- This decrease in DPM availability impairs O-mannosylation of alpha-dystroglycan in skeletal muscle.
- The patient exhibited a mild limb girdle muscular dystrophy phenotype without cardiomyopathy.
Implications:
- DPM3 mutations can result in isolated limb girdle muscular dystrophy.
- This expands the known phenotypic spectrum of DPM3-associated muscular dystrophies.
- Understanding these genetic underpinnings is crucial for diagnosis and potential therapeutic strategies.
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