Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies.
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.
Lefeber
Dirk J
DJ
Laboratory of Pediatrics & Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. d.lefeber@cukz.umcn.nl
Schönberger
Johannes
J
Morava
Eva
E
Guillard
Mailys
M
Huyben
Karin M
KM
Verrijp
Kiek
K
Grafakou
Olga
O
Evangeliou
Athanasios
A
Preijers
Frank W
FW
Manta
Panagiota
P
Yildiz
Jef
J
Grünewald
Stephanie
S
Spilioti
Martha
M
van den Elzen
Christa
C
Klein
Dominique
D
Hess
Daniel
D
Ashida
Hisashi
H
Hofsteenge
Jan
J
Maeda
Yusuke
Y
van den Heuvel
Lambert
L
Lammens
Martin
M
Lehle
Ludwig
L
Wevers
Ron A
RA
D004287:Dolichol Monophosphate Mannose / Q000378:metabolism*; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D008364:Mannosyltransferases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism*
D008565:Membrane Proteins; D049030:Dystroglycans; D004287:Dolichol Monophosphate Mannose; D008364:Mannosyltransferases; C429687:DPM3 protein, human