Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome.
Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (αDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective αDG glycosylation and reduced ligand binding by αDG causing a clinically heterogeneous group of congenital muscular dystrophies, commonly referred to as dystroglycanopathies. The most severe clinical form, Walker-Warburg syndrome (WWS), is characterized by congenital muscular dystrophy and severe neurological and ophthalmological defects. Here, we report two homozygous missense mutations in the β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) gene in a family affected with WWS. Functional studies confirmed the pathogenicity of the mutations. First, expression of wild-type but not mutant B3GNT1 in human prostate cancer (PC3) cells led to increased levels of αDG glycosylation. Second, morpholino knockdown of the zebrafish b3gnt1 orthologue caused characteristic muscular defects and reduced αDG glycosylation. These functional studies identify an important role of B3GNT1 in the synthesis of the uncharacterized laminin-binding glycan of αDG and implicate B3GNT1 as a novel causative gene for WWS.
Department of Human Genetics 855, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Karen
K
Buysse
Moniek
M
Riemersma
Gareth
G
Powell
Jeroen
J
van Reeuwijk
David
D
Chitayat
Tony
T
Roscioli
Erik-Jan
EJ
Kamsteeg
Christa
C
van den Elzen
Ellen
E
van Beusekom
Susan
S
Blaser
Riyana
R
Babul-Hirji
William
W
Halliday
Gavin J
GJ
Wright
Derek L
DL
Stemple
Yung-Yao
YY
Lin
Dirk J
DJ
Lefeber
Hans
H
van Bokhoven
D000818:Animals; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D015331:Cohort Studies; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D007223:Infant; D007797:Laminin / Q000378:metabolism; D008297:Male; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics; D020125:Mutation, Missense; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000473:pathology; D015027:Zebrafish / Q000235:genetics
D007797:Laminin; D049030:Dystroglycans; D017351:N-Acetylglucosaminyltransferases; C542575:B4GAT1 protein, human