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Abstract
Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioritization of candidate genes in this locus for a role in CHDs identified the TGF-beta-activated kinase 1/MAP3K7 binding protein 2 gene (TAB2) as the top-ranking candidate gene. A role for this candidate gene in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos. To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CL-ID. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAR2 in human cardiac development.
Keywords
SCIENTIFIC STATEMENT, VASCULAR DEVELOPMENT, CARDIOVASCULAR-DISEASE, MENTAL-RETARDATION, CLINICAL-FEATURES, CURRENT KNOWLEDGE, GROWTH FAILURE, IN-VIVO, IDENTIFICATION, HYBRIDIZATION

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Chicago
Thienpont, Bernard, Litu Zhang, Alex V Postma, Jeroen Breckpot, Leon-Charles Tranchevent, Peter Van Loo, Kjedl Mollgard, et al. 2010. “Haploinsufficiency of TAB2 Causes Congenital Heart Defects in Humans.” American Journal of Human Genetics 86 (6): 839–849.
APA
Thienpont, Bernard, Zhang, L., Postma, A. V., Breckpot, J., Tranchevent, L.-C., Van Loo, P., Mollgard, K., et al. (2010). Haploinsufficiency of TAB2 causes congenital heart defects in humans. AMERICAN JOURNAL OF HUMAN GENETICS, 86(6), 839–849.
Vancouver
1.
Thienpont B, Zhang L, Postma AV, Breckpot J, Tranchevent L-C, Van Loo P, et al. Haploinsufficiency of TAB2 causes congenital heart defects in humans. AMERICAN JOURNAL OF HUMAN GENETICS. 2010;86(6):839–49.
MLA
Thienpont, Bernard, Litu Zhang, Alex V Postma, et al. “Haploinsufficiency of TAB2 Causes Congenital Heart Defects in Humans.” AMERICAN JOURNAL OF HUMAN GENETICS 86.6 (2010): 839–849. Print.
@article{1163149,
  abstract     = {Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioritization of candidate genes in this locus for a role in CHDs identified the TGF-beta-activated kinase 1/MAP3K7 binding protein 2 gene (TAB2) as the top-ranking candidate gene. A role for this candidate gene in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos. To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CL-ID. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAR2 in human cardiac development.},
  author       = {Thienpont, Bernard and Zhang, Litu and Postma, Alex V and Breckpot, Jeroen and Tranchevent, Leon-Charles and Van Loo, Peter and Mollgard, Kjedl and Tommerup, Niels and Bache, Iben and Tumer, Zeynep and van Engelen, Klaartje and Menten, Bj{\"o}rn and Mortier, Geert and Waggoner, Darrel and Gewillig, Marc and Moreau, Yves and Devriendt, Koen and Larsen, Lars Allan},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {SCIENTIFIC STATEMENT,VASCULAR DEVELOPMENT,CARDIOVASCULAR-DISEASE,MENTAL-RETARDATION,CLINICAL-FEATURES,CURRENT KNOWLEDGE,GROWTH FAILURE,IN-VIVO,IDENTIFICATION,HYBRIDIZATION},
  language     = {eng},
  number       = {6},
  pages        = {839--849},
  title        = {Haploinsufficiency of TAB2 causes congenital heart defects in humans},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2010.04.011},
  volume       = {86},
  year         = {2010},
}

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