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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan
American Journal of Human Genetics, Volume 92, No. 3, Year 2013
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Description
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. © 2013 The American Society of Human Genetics.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3591840/bin/mmc1.pdf
Authors & Co-Authors
Stevens, Elizabeth
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Carss, Keren J.
United Kingdom, Hinxton
Wellcome Sanger Institute
Cirak, Sebahattin
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Foley, A. Reghan
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Torelli, Silvia
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Willer, Tobias
United States, Iowa City
University of Iowa
Tambunan, Dimira E.
United States, Boston
Boston Children's Hospital
Yau, Shu
United Kingdom, London
Dna Laboratory
Brodd, Lina
United Kingdom, London
Dna Laboratory
Sewry, Caroline A.
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
United Kingdom, Oswestry
Centre for Inherited Neuromuscular Disorders
Feng, Lucy
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Haliloglu, Göknur
Turkey, Ankara
Hacettepe Üniversitesi
Orhan, Diclehan
Turkey, Ankara
Hacettepe Üniversitesi
Dobyns, William B.
United States, Seattle
Seattle Children's Hospital
Enns, Gregory M.
United States, Stanford
Stanford University School of Medicine
Manning, Melanie Ann
United States, Stanford
Stanford University School of Medicine
Krause, Amanda
South Africa, Johannesburg
School of Pathology
Salih, Mustafa Abdalla M.
Saudi Arabia, Riyadh
College of Medicine
Walsh, Christopher A.
United States, Boston
Boston Children's Hospital
Hurles, Matthew E.
United Kingdom, Hinxton
Wellcome Sanger Institute
Campbell, Kevin P.
United States, Iowa City
University of Iowa
Manzini, M. Chiara
United States, Boston
Boston Children's Hospital
Stemple, Derek L.
United Kingdom, Hinxton
Wellcome Sanger Institute
Lin, Yung Yao
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Muntoni, Francesco M.
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Statistics
Citations: 170
Authors: 25
Affiliations: 12
Identifiers
Doi:
10.1016/j.ajhg.2013.01.016
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Disability
Genetics And Genomics
Study Design
Cohort Study