title: Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan.
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.
authors: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors: Elizabeth
authors: E
authors: Stevens
authors: Keren J
authors: KJ
authors: Carss
authors: Sebahattin
authors: S
authors: Cirak
authors: A Reghan
authors: AR
authors: Foley
authors: Silvia
authors: S
authors: Torelli
authors: Tobias
authors: T
authors: Willer
authors: Dimira E
authors: DE
authors: Tambunan
authors: Shu
authors: S
authors: Yau
authors: Lina
authors: L
authors: Brodd
authors: Caroline A
authors: CA
authors: Sewry
authors: Lucy
authors: L
authors: Feng
authors: Goknur
authors: G
authors: Haliloglu
authors: Diclehan
authors: D
authors: Orhan
authors: William B
authors: WB
authors: Dobyns
authors: Gregory M
authors: GM
authors: Enns
authors: Melanie
authors: M
authors: Manning
authors: Amanda
authors: A
authors: Krause
authors: Mustafa A
authors: MA
authors: Salih
authors: Christopher A
authors: CA
authors: Walsh
authors: Matthew
authors: M
authors: Hurles
authors: Kevin P
authors: KP
authors: Campbell
authors: M Chiara
authors: MC
authors: Manzini
authors: Derek
authors: D
authors: Stemple
authors: Yung-Yao
authors: YY
authors: Lin
authors: Francesco
authors: F
authors: Muntoni
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D049030:Dystroglycans / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D007223:Infant; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009136:Muscular Dystrophies / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D049030:Dystroglycans; D017350:N-Acetylgalactosaminyltransferases