Title: Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies
Authors: Lefeber, Dirk J ×
Schönberger, Johannes
Morava, Eva
Guillard, Mailys
Huyben, Karin M
Verrijp, Kiek
Grafakou, Olga
Evangeliou, Athanasios
Preijers, Frank W
Manta, Panagiota
Yildiz, Jef
Grünewald, Stephanie
Spilioti, Martha
van den Elzen, Christa
Klein, Dominique
Hess, Daniel
Ashida, Hisashi
Hofsteenge, Jan
Maeda, Yusuke
van den Heuvel, Lambertus
Lammens, Martin
Lehle, Ludwig
Wevers, Ron A #
Issue Date: Jul-2009
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:85 issue:1 pages:76-86
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.
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

Files in This Item:

There are no files associated with this item.

Request a copy


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science