Περίληψη:
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.
Συγγραφείς:
Lefeber, D.J.
Schönberger, J.
Morava, E.
Guillard, M.
Huyben, K.M.
Verrijp, K.
Grafakou, O.
Evangeliou, A.
Preijers, F.W.
Manta, P.
Yildiz, J.
Grünewald, S.
Spilioti, M.
van den Elzen, C.
Klein, D.
Hess, D.
Ashida, H.
Hofsteenge, J.
Maeda, Y.
van den Heuvel, L.
Lammens, M.
Lehle, L.
Wevers, R.A.
Λέξεις-κλειδιά:
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
