Journal article
Mutations in B3GALNT2 Cause Congenital Muscular Dystrophy and Hypoglycosylation of α-Dystroglycan
American journal of human genetics, Vol.92(3), pp.354-365
03/07/2013
DOI: 10.1016/j.ajhg.2013.01.016
PMCID: PMC3591840
PMID: 23453667
Abstract
Mutations in several known or putative glycosyltransferases cause glycosylation defects in α-dystroglycan (α-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of α-DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in β-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a β-1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of α-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement.
Details
- Title: Subtitle
- Mutations in B3GALNT2 Cause Congenital Muscular Dystrophy and Hypoglycosylation of α-Dystroglycan
- Creators
- Elizabeth Stevens - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKKeren J Carss - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKSebahattin Cirak - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKA. Reghan Foley - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKSilvia Torelli - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKTobias Willer - Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USADimira E Tambunan - Division of Genetics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USAShu Yau - DNA Laboratory, GSTS Pathology, London SE1 9RT, UKLina Brodd - DNA Laboratory, GSTS Pathology, London SE1 9RT, UKCaroline A Sewry - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKLucy Feng - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UKGoknur Haliloglu - Faculty of Medicine, Department of Paediatric Neurology, Hacettepe University, Ankara 06100, TurkeyDiclehan Orhan - Faculty of Medicine, Department of Paediatric Neurology, Hacettepe University, Ankara 06100, TurkeyWilliam B Dobyns - Center for Integrative Brain Research, Seattle Children’s Hospital, Seattle, WA 98105, USAGregory M Enns - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304, USAMelanie Manning - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304, USAAmanda Krause - Division of Human Genetics, National Health Laboratory Service and School of Pathology, the University of the Witwatersrand, Johannesburg 2000, South AfricaMustafa A Salih - Division of Pediatric Neurology, Department of Pediatrics, King Saud University College of Medicine, Riyadh 11461, Saudi ArabiaChristopher A Walsh - Division of Genetics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USAMatthew Hurles - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKKevin P Campbell - Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USAM. Chiara Manzini - Division of Genetics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USADerek Stemple - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKYung-Yao Lin - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UKFrancesco Muntoni - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London WC1N 1EH, UK
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.92(3), pp.354-365
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ajhg.2013.01.016
- PMID
- 23453667
- PMCID
- PMC3591840
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Language
- English
- Date published
- 03/07/2013
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020849602771
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