NDLI: Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies

Content Provider	PubMed Central
Author	Lefeber, Dirk J. Schönberger, Johannes Morava, Eva Guillard, Mailys Huyben, Karin M. Verrijp, Kiek Olga, Grafakou Athanasios, Evangeliou Preijers, Frank W. Manta, Panagiota Yildiz, Jef Grünewald, Stephanie Martha, Spilioti Den Elzen, Christa Van Klein, Dominique Hess, Daniel Ashida, Hisashi Jan, Hofsteenge Maeda, Yusuke Heuvel, Lambert Van Den Lammens, Martin Lehle, Ludwig Wevers, Ron A.
Copyright Year	2009
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.
Related Links	http://dx.doi.org/10.1016/j.ajhg.2009.06.006
Ending Page	86
Page Count	11
Starting Page	76
File Format	PDF
ISSN	00029297
e-ISSN	15376605
Journal	American Journal of Human Genetics
Issue Number	1
Volume Number	85
Language	English
Publisher	Elsevier
Publisher Date	2009-07-01
Access Restriction	Open
Rights Holder	Elsevier
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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