TY - JOUR
TI - Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies
AU - Lefeber, D.J.
AU - Schönberger, J.
AU - Morava, E.
AU - Guillard, M.
AU - Huyben, K.M.
AU - Verrijp, K.
AU - Grafakou, O.
AU - Evangeliou, A.
AU - Preijers, F.W.
AU - Manta, P.
AU - Yildiz, J.
AU - Grünewald, S.
AU - Spilioti, M.
AU - van den Elzen, C.
AU - Klein, D.
AU - Hess, D.
AU - Ashida, H.
AU - Hofsteenge, J.
AU - Maeda, Y.
AU - van den Heuvel, L.
AU - Lammens, M.
AU - Lehle, L.
AU - Wevers, R.A.
JO - American Journal of Human Genetics
PY - 2009
VL - 85
TODO - 1
SP - 76-86
PB - 
SN - 0002-9297, 1537-6605
TODO - 10.1016/j.ajhg.2009.06.006
TODO - alpha dystroglycan;  dolichol phosphate mannose, animal cell;  article;  catalysis;  cell membrane;  congenital disorder;  controlled study;  dystroglycanopathy;  endoplasmic reticulum;  enzyme activity;  female;  gene sequence;  genetic transfection;  glycosylation;  human;  missense mutation;  muscular dystrophy;  nonhuman;  phenotype;  priority journal;  protein binding;  protein deficiency;  protein synthesis, Dolichol Monophosphate Mannose;  Dystroglycans;  Female;  Glycosylation;  Humans;  Mannosyltransferases;  Membrane Proteins;  Muscular Dystrophies
TODO - 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. © 2009 The American Society of Human Genetics.
ER -