TY - JOUR
T1 - Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies
AU - Lefeber, Dirk J.
AU - Schönberger, Johannes
AU - Morava, Eva
AU - Guillard, Mailys
AU - Huyben, Karin M.
AU - Verrijp, Kiek
AU - Grafakou, Olga
AU - Evangeliou, Athanasios
AU - Preijers, Frank W.
AU - Manta, Panagiota
AU - Yildiz, Jef
AU - Grünewald, Stephanie
AU - Spilioti, Martha
AU - van den Elzen, Christa
AU - Klein, Dominique
AU - Hess, Daniel
AU - Ashida, Hisashi
AU - Hofsteenge, Jan
AU - Maeda, Yusuke
AU - van den Heuvel, Lambert
AU - Lammens, Martin
AU - Lehle, Ludwig
AU - Wevers, Ron A.
N1 - Funding Information:
We would like to acknowledge the parents of the CDG-Ie patient and M. Garcia-Silva for providing the CDG-Ie fibroblast reference cell line. We gratefully acknowledge K. Campbell for the kind gift of IIH6 antibody. LC-MS experiments of immunopurified transferrin were performed by J. O'Brien. K. Huyben, K. Verrijp, and E. van Kaauwen are acknowledged for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Körber-Stiftung to L.L. and Euroglycanet (LSHM-CT2005-512131) and Metakids to D.J.L. and R.A.W. The work at the Friedrich Miescher Institute was supported by the Novartis Research Foundation.
PY - 2009/7/10
Y1 - 2009/7/10
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2009.06.006
DO - 10.1016/j.ajhg.2009.06.006
M3 - Article
C2 - 19576565
AN - SCOPUS:67649584051
SN - 0002-9297
VL - 85
SP - 76
EP - 86
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -