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

摘要

Highlights ? Dolichol-P-mannose (DPM) synthase is essential for alpha-dystroglycan O-glycosylation. ? DPM synthase is composed of 3 subunits (DPM1, DPM2, and DPM3). ? DPM synthase mutations cause congenital muscular dystrophy with or without brain involvement. ? Mutations in DPM3 can cause isolated, mild 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.