@article{3089123,
    title = "Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies",
    author = "Lefeber, D.J. and Schönberger, J. and Morava, E. and Guillard, M. and Huyben, K.M. and Verrijp, K. and Grafakou, O. and Evangeliou, A. and Preijers, F.W. and Manta, P. and Yildiz, J. and Grünewald, S. and Spilioti, M. and van den Elzen, C. and Klein, D. and Hess, D. and Ashida, H. and Hofsteenge, J. and Maeda, Y. and van den Heuvel, L. and Lammens, M. and Lehle, L. and Wevers, R.A.",
    journal = "American Journal of Human Genetics",
    year = "2009",
    volume = "85",
    number = "1",
    pages = "76-86",
    issn = "0002-9297, 1537-6605",
    doi = "10.1016/j.ajhg.2009.06.006",
    keywords = "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",
    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. © 2009 The American Society of Human Genetics."
}