TY - JOUR
TI - Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG
AU - van Tol, W.
AU - Michelakakis, H.
AU - Georgiadou, E.
AU - van den Bergh, P.
AU - Moraitou, M.
AU - Papadimas, G.K.
AU - Papadopoulos, C.
AU - Huijben, K.
AU - Alsady, M.
AU - Willemsen, M.A.
AU - Lefeber, D.J.
JO - Journal of Inherited Metabolic Disease
PY - 2019
VL - 42
TODO - 5
SP - 984-992
PB - John Wiley and Sons Inc
SN - 0141-8955
TODO - 10.1002/jimd.12095
TODO - beta dystroglycan;  glycan;  guanosine diphosphate mannose pyrophosphorylase B;  phosphorylase;  unclassified drug;  DPM3 protein, human;  dystroglycan;  mannosyltransferase;  membrane protein, adult;  Article;  child;  clinical article;  clinical feature;  congenital disorder of glycosylation;  dolicholphosphate mannose synthesis disorder;  female;  glycosylation;  human;  human cell;  human tissue;  inborn error of metabolism;  middle aged;  mutational analysis;  pathophysiology;  phenotype;  skeletal muscle;  symptom;  Western blotting;  biopsy;  congenital disorder of glycosylation;  genetics;  male;  metabolism;  muscular dystrophy;  mutation;  pathology, Adult;  Biopsy;  Child;  Congenital Disorders of Glycosylation;  Dystroglycans;  Female;  Glycosylation;  Humans;  Male;  Mannosyltransferases;  Membrane Proteins;  Middle Aged;  Muscle, Skeletal;  Muscular Dystrophies;  Mutation;  Phenotype
TODO - 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. © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM
ER -