title: Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies.
abstract: Alpha-dystroglycanopathies such as Walker Warburg syndrome represent an important subgroup of the muscular dystrophies that have been related to defective O-mannosylation of alpha-dystroglycan. In many patients, the underlying genetic etiology remains unsolved. Isolated muscular dystrophy has not been described in the congenital disorders of glycosylation (CDG) caused by N-linked protein glycosylation defects. Here, we present a genetic N-glycosylation disorder with muscular dystrophy in the group of CDG type I. Extensive biochemical investigations revealed a strongly reduced dolichol-phosphate-mannose (Dol-P-Man) synthase activity. Sequencing of the three DPM subunits and complementation of DPM3-deficient CHO2.38 cells showed a pathogenic p.L85S missense mutation in the strongly conserved coiled-coil domain of DPM3 that tethers catalytic DPM1 to the ER membrane. Cotransfection experiments in CHO cells showed a reduced binding capacity of DPM3(L85S) for DPM1. Investigation of the four Dol-P-Man-dependent glycosylation pathways in the ER revealed strongly reduced O-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy. This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies.
authors: Laboratory of Pediatrics & Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. d.lefeber@cukz.umcn.nl
authors: Dirk J
authors: DJ
authors: Lefeber
authors: Johannes
authors: J
authors: Schönberger
authors: Eva
authors: E
authors: Morava
authors: Mailys
authors: M
authors: Guillard
authors: Karin M
authors: KM
authors: Huyben
authors: Kiek
authors: K
authors: Verrijp
authors: Olga
authors: O
authors: Grafakou
authors: Athanasios
authors: A
authors: Evangeliou
authors: Frank W
authors: FW
authors: Preijers
authors: Panagiota
authors: P
authors: Manta
authors: Jef
authors: J
authors: Yildiz
authors: Stephanie
authors: S
authors: Grünewald
authors: Martha
authors: M
authors: Spilioti
authors: Christa
authors: C
authors: van den Elzen
authors: Dominique
authors: D
authors: Klein
authors: Daniel
authors: D
authors: Hess
authors: Hisashi
authors: H
authors: Ashida
authors: Jan
authors: J
authors: Hofsteenge
authors: Yusuke
authors: Y
authors: Maeda
authors: Lambert
authors: L
authors: van den Heuvel
authors: Martin
authors: M
authors: Lammens
authors: Ludwig
authors: L
authors: Lehle
authors: Ron A
authors: RA
authors: Wevers
mesh_terms: D004287:Dolichol Monophosphate Mannose / Q000378:metabolism*; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D008364:Mannosyltransferases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D049030:Dystroglycans; D004287:Dolichol Monophosphate Mannose; D008364:Mannosyltransferases; C429687:DPM3 protein, human