Toward understanding tissue‐specific symptoms in dolichol‐phosphate‐mannose synthesis disorders; insight from DPM3‐CDG

The congenital disorders of glycosylation (CDG) are inborn errors of metabolism with a great genetic heterogeneity. Most CDG are caused by defects in the N‐glycan biosynthesis, leading to multisystem phenotypes. However, the occurrence of tissue‐restricted clinical symptoms in the various defects in dolichol‐phosphate‐mannose (DPM) synthesis remains unexplained. To deepen our understanding of the tissue‐specific characteristics of defects in the DPM synthesis pathway, we investigated N‐glycosylation and O‐mannosylation in skeletal muscle of three DPM3‐CDG patients presenting with muscle dystrophy and hypo‐N‐glycosylation of serum transferrin in only two of them. In the three patients, O‐mannosylation of alpha‐dystroglycan (αDG) was strongly reduced and western blot analysis of beta‐dystroglycan (βDG) N‐glycosylation revealed a consistent lack of one N‐glycan in skeletal muscle. Recently, defective N‐glycosylation of βDG has been reported in patients with mutations in guanosine‐diphosphate‐mannose pyrophosphorylase B (GMPPB). Thus, we suggest that aberrant O‐glycosylation of αDG and N‐glycosylation of βDG in skeletal muscle is indicative of a defect in the DPM synthesis pathway. Further studies should address to what extent hypo‐N‐glycosylation of βDG or other skeletal muscle proteins contribute to the phenotype of patients with defects in DPM synthesis. Our findings contribute to our understanding of the tissue‐restricted phenotype of DPM3‐CDG and other defects in the DPM synthesis pathway.