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...

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Main Authors:	Buysse, Karen, Riemersma, Moniek, Powell, Gareth, van Reeuwijk, Jeroen, Chitayat, David, Roscioli, Tony, Kamsteeg, Erik-Jan, van den Elzen, Christa, van Beusekom, Ellen, Blaser, Susan, Babul-Hirji, Riyana, Halliday, William, Wright, Gavin J., Stemple, Derek L., Lin, Yung-Yao, Lefeber, Dirk J., van Bokhoven, Hans
Format:	Online
Language:	English
Published:	Oxford University Press 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613162/

id	pubmed-3613162
recordtype	oai_dc
spelling	pubmed-36131622013-04-03 Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome Buysse, Karen Riemersma, Moniek Powell, Gareth van Reeuwijk, Jeroen Chitayat, David Roscioli, Tony Kamsteeg, Erik-Jan van den Elzen, Christa van Beusekom, Ellen Blaser, Susan Babul-Hirji, Riyana Halliday, William Wright, Gavin J. Stemple, Derek L. Lin, Yung-Yao Lefeber, Dirk J. van Bokhoven, Hans Articles 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. Oxford University Press 2013-05-01 2013-01-28 /pmc/articles/PMC3613162/ /pubmed/23359570 http://dx.doi.org/10.1093/hmg/ddt021 Text en © The Author 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permission@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Buysse, Karen Riemersma, Moniek Powell, Gareth van Reeuwijk, Jeroen Chitayat, David Roscioli, Tony Kamsteeg, Erik-Jan van den Elzen, Christa van Beusekom, Ellen Blaser, Susan Babul-Hirji, Riyana Halliday, William Wright, Gavin J. Stemple, Derek L. Lin, Yung-Yao Lefeber, Dirk J. van Bokhoven, Hans
spellingShingle	Buysse, Karen Riemersma, Moniek Powell, Gareth van Reeuwijk, Jeroen Chitayat, David Roscioli, Tony Kamsteeg, Erik-Jan van den Elzen, Christa van Beusekom, Ellen Blaser, Susan Babul-Hirji, Riyana Halliday, William Wright, Gavin J. Stemple, Derek L. Lin, Yung-Yao Lefeber, Dirk J. van Bokhoven, Hans Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
author_facet	Buysse, Karen Riemersma, Moniek Powell, Gareth van Reeuwijk, Jeroen Chitayat, David Roscioli, Tony Kamsteeg, Erik-Jan van den Elzen, Christa van Beusekom, Ellen Blaser, Susan Babul-Hirji, Riyana Halliday, William Wright, Gavin J. Stemple, Derek L. Lin, Yung-Yao Lefeber, Dirk J. van Bokhoven, Hans
author_sort	Buysse, Karen
title	Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
title_short	Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
title_full	Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
title_fullStr	Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
title_full_unstemmed	Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome
title_sort	missense mutations in β-1,3-n-acetylglucosaminyltransferase 1 (b3gnt1) cause walker–warburg syndrome
description	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.
publisher	Oxford University Press
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613162/
_version_	1611966587318829056

Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome

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