Τίτλος:
Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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
Συγγραφείς:
van Tol, W.
Michelakakis, H.
Georgiadou, E.
van den Bergh, P.
Moraitou, M.
Papadimas, G.K.
Papadopoulos, C.
Huijben, K.
Alsady, M.
Willemsen, M.A.
Lefeber, D.J.
Περιοδικό:
Journal of Inherited Metabolic Disease
Εκδότης:
John Wiley and Sons Inc
Λέξεις-κλειδιά:
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
