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Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies |
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| Authors: | Dirk J Lefeber Johannes Schönberger Eva Morava Karin M Huyben Olga Grafakou Frank W Preijers Jef Yildiz Martha Spilioti Dominique Klein Hisashi Ashida Yusuke Maeda Martin Lammens Ron A Wevers |
| Institution: | 1 Laboratory of Pediatrics & Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands 2 Department of Pediatrics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands 3 Department of Pathology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands 4 Central Hematology Laboratory, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands 5 Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands 6 Universitaet Regensburg, 93053 Regensburg, Germany 7 Department of Pediatrics, Rethymnon General Hospital, Rethymnon 74100, Greece 8 Fourth Pediatric Clinic of the Aristotelian University of Thessaloniki, Papageorgiou Hospital, Thessaloniki GR-56403, Greece 9 Department of Neurology, University of Athens, Athens 11528, Greece 10 Great Ormond Street Hospital, London WC1N 1EH, UK 11 Department of Neurology, University of Crete, 71003 Heraklion-Crete, Greece 12 Friedrich Miescher Institute, 4058 Basel, Switzerland 13 Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan 14 WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan |
| 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. |
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