PMID- 23453667
OWN - NLM
STAT- MEDLINE
DCOM- 20130729
LR  - 20231115
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 92
IP  - 3
DP  - 2013 Mar 7
TI  - Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation 
      of alpha-dystroglycan.
PG  - 354-65
LID - S0002-9297(13)00069-4 [pii]
LID - 10.1016/j.ajhg.2013.01.016 [doi]
AB  - Mutations in several known or putative glycosyltransferases cause glycosylation 
      defects in alpha-dystroglycan (alpha-DG), an integral component of the dystrophin 
      glycoprotein complex. The hypoglycosylation reduces the ability of alpha-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 
      beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl 
      galactosamine (GalNAc) in a beta-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 
      alpha-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle 
      and brain involvement.
CI  - Copyright (c) 2013 The American Society of Human Genetics. Published by Elsevier 
      Inc. All rights reserved.
FAU - Stevens, Elizabeth
AU  - Stevens E
AD  - Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
FAU - Carss, Keren J
AU  - Carss KJ
FAU - Cirak, Sebahattin
AU  - Cirak S
FAU - Foley, A Reghan
AU  - Foley AR
FAU - Torelli, Silvia
AU  - Torelli S
FAU - Willer, Tobias
AU  - Willer T
FAU - Tambunan, Dimira E
AU  - Tambunan DE
FAU - Yau, Shu
AU  - Yau S
FAU - Brodd, Lina
AU  - Brodd L
FAU - Sewry, Caroline A
AU  - Sewry CA
FAU - Feng, Lucy
AU  - Feng L
FAU - Haliloglu, Goknur
AU  - Haliloglu G
FAU - Orhan, Diclehan
AU  - Orhan D
FAU - Dobyns, William B
AU  - Dobyns WB
FAU - Enns, Gregory M
AU  - Enns GM
FAU - Manning, Melanie
AU  - Manning M
FAU - Krause, Amanda
AU  - Krause A
FAU - Salih, Mustafa A
AU  - Salih MA
FAU - Walsh, Christopher A
AU  - Walsh CA
FAU - Hurles, Matthew
AU  - Hurles M
FAU - Campbell, Kevin P
AU  - Campbell KP
FAU - Manzini, M Chiara
AU  - Manzini MC
CN  - UK10K Consortium
FAU - Stemple, Derek
AU  - Stemple D
FAU - Lin, Yung-Yao
AU  - Lin YY
FAU - Muntoni, Francesco
AU  - Muntoni F
LA  - eng
GR  - RC2MH089952/MH/NIMH NIH HHS/United States
GR  - MR/K000608/1/MRC_/Medical Research Council/United Kingdom
GR  - RC2 MH089952/MH/NIMH NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - U54 NS053672/NS/NINDS NIH HHS/United States
GR  - K99 HD067379/HD/NICHD NIH HHS/United States
GR  - K99HD067379/HD/NICHD NIH HHS/United States
GR  - 1U54NS053672/NS/NINDS NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - P30HD19655/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, American Recovery and Reinvestment Act
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130228
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 146888-27-9 (Dystroglycans)
RN  - EC 2.4.1.- (N-Acetylgalactosaminyltransferases)
SB  - IM
MH  - Animals
MH  - Brain/enzymology/metabolism
MH  - Cell Line
MH  - Dystroglycans/*genetics/metabolism
MH  - Endoplasmic Reticulum/enzymology/genetics/metabolism
MH  - Female
MH  - Fibroblasts/enzymology/metabolism
MH  - Genetic Predisposition to Disease
MH  - Glycosylation
MH  - Humans
MH  - Infant
MH  - Male
MH  - Muscle, Skeletal/enzymology/metabolism
MH  - Muscular Dystrophies/enzymology/*genetics/metabolism
MH  - *Mutation
MH  - N-Acetylgalactosaminyltransferases/*genetics/metabolism
MH  - Zebrafish
PMC - PMC3591840
EDAT- 2013/03/05 06:00
MHDA- 2013/07/31 06:00
PMCR- 2013/09/07
CRDT- 2013/03/05 06:00
PHST- 2012/08/30 00:00 [received]
PHST- 2012/10/29 00:00 [revised]
PHST- 2013/01/22 00:00 [accepted]
PHST- 2013/03/05 06:00 [entrez]
PHST- 2013/03/05 06:00 [pubmed]
PHST- 2013/07/31 06:00 [medline]
PHST- 2013/09/07 00:00 [pmc-release]
AID - S0002-9297(13)00069-4 [pii]
AID - 10.1016/j.ajhg.2013.01.016 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2013 Mar 7;92(3):354-65. doi: 10.1016/j.ajhg.2013.01.016. Epub 
      2013 Feb 28.