TY - JOUR
T1 - Haploinsufficiency of TAB2 Causes Congenital Heart Defects in Humans
AU - Thienpont, Bernard
AU - Zhang, Litu
AU - Postma, Alex V.
AU - Breckpot, Jeroen
AU - Tranchevent, Léon Charles
AU - Van Loo, Peter
AU - Møllgård, Kjeld
AU - Tommerup, Niels
AU - Bache, Iben
AU - Tümer, Zeynep
AU - van Engelen, Klaartje
AU - Menten, Björn
AU - Mortier, Geert
AU - Waggoner, Darrel
AU - Gewillig, Marc
AU - Moreau, Yves
AU - Devriendt, Koen
AU - Larsen, Lars Allan
N1 - Funding Information: B.T. is supported by a Ph.D. fellowship from the Agentschap voor Innovatie door Wetenschap en Technologie (IWT). P.V.L. is a postdoctoral researcher, K.D. a senior clinical investigator, and J.B. an aspirant investigator of the Research Foundation-Flanders (FWO). L.A.L. is supported by The Danish Heart Foundation and The Novo Nordisk Foundation. This work was supported by OT/O2/40, GOA/2006/12, Centre of Excellence SymBioSys (EF/05/007) from the University of Leuven and from the Belgian program of Interuniversity Poles of Attraction (IUAP), ProMeta, GOA Ambiorics, GOA MaNet, START 1, FWO (G.0318.05, G.0254.05, G.0553.06, G.0302.07, ICCoS, ANMMM, MLDM, G.0733.09, G.082409), IWT (Silicos, SBO-BioFrame, SBO-MoKa, TBM-IOTA3), IUAP P6/25 BioMaGNet, ERNSI (FP7-HEALTH CHeartED). The Wilhelm Johannsen Centre for Functional Genome Research is established by the Danish National Research Foundation. We thank D. Stainier for sharing the transgenic flk-GFP zebrafish, S. Forschhammer and A. Ilgun for technical assistance, and the Leuven Aquatic Facility for excellent fish care. Copyright: Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/7/11
Y1 - 2010/7/11
N2 - 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-β-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 CHD. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development.
AB - 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-β-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 CHD. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development.
UR - http://www.scopus.com/inward/record.url?scp=77953231502&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2010.04.011
DO - https://doi.org/10.1016/j.ajhg.2010.04.011
M3 - Article
C2 - 20493459
SN - 0002-9297
VL - 86
SP - 839
EP - 849
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -