Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan

Elizabeth Stevens, Keren J. Carss, Sebahattin Cirak, A. Reghan Foley, Silvia Torelli, Tobias Willer, Dimira E. Tambunan, Shu Yau, Lina Brodd, Caroline A. Sewry, Lucy Feng, Goknur Haliloglu, Diclehan Orhan, William B. Dobyns, Gregory M. Enns, Melanie Manning, Amanda Krause, Mustafa A. Salih, Christopher A. Walsh, Matthew HurlesKevin P. Campbell, M. Chiara Manzini, Derek Stemple, Yung Yao Lin, Francesco Muntoni

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)354-365
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - Mar 7 2013
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to the UK10K consortium for making this study possible. We wish to thank the following funding bodies: the UK National Specialised Commissioned Team funding for the Congenital Muscular Dystrophies and Congenital Myopathy service, the Great Ormond Street Children’s Charity and the GOSH Biomedical Research Centre (F.M.), the Paul D. Wellstone Muscular Dystrophy Cooperative Research Centre Grant (1U54NS053672; K.P.C., T.W., and F.M.), and the Medical Research Council (MRC) Neuromuscular Centre (F.M.). E.S. is a PhD student supported by the MRC, Great Ormond Street Children’s Charity, and the Child Health Research Appeal Trust (CHRAT) (F.M.). K.J.C. is a PhD student supported by the Wellcome Trust. A.R.F. is a Clinical Research Fellow supported by the Muscular Dystrophy Campaign (F.M.). M.C.M. was supported by a Development Grant from the Muscular Dystrophy Association and by the William Randolph Hearst Fund and is currently the recipient of a Junior Faculty Career Development Award from the Manton Centre for Orphan Disease Research and a K99/R00 Transition to Independence award from the NIH (NICHD, K99HD067379). Sequencing at Boston Children’s Hospital was supported by the Intellectual and Developmental Disabilities Research Centres (CHB DDRC, P30HD19655). Sequencing at the Broad Institute was supported by a grant from NIH and the American Recovery & Reinvestment Act (NIMH RC2MH089952). K.P.C. and C.A.W. are Investigators of the Howard Hughes Medical Institute. We are very grateful to A. Eddaoudi and his team for their excellent support of the flow cytometry core facility at Great Ormond Street Hospital.


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