Title: Haplo-insufficiency of TAB2 causes congenital heart defects in humans
Authors: Thienpont, Bernard
Zhang, L
Postma, A.V
Breckpot, Jeroen
Tranchevent, Léon-Charles
Van Loo, Peter
Mollgard, K
Tommerup, N
Bache, I
Tumer, Z
Van Engelen, K
Menten, B
Mortier, G
Waggoner, D
Gewillig, Marc
Moreau, Yves
Devriendt, Koenraad
Larsen, L.A # ×
Issue Date: Jun-2010
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:86 issue:6 pages:839-849
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 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.
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Translational Genetics (Vesalius Research Center) (+)
ESAT - STADIUS, Stadius Centre for Dynamical Systems, Signal Processing and Data Analytics
Laboratory for Genetics of Human Development
Human Genome Laboratory
Pediatric Cardiology Section (-)
Department of Human Genetics - miscellaneous
Cardiovascular Developmental Biology
× corresponding author
# (joint) last author

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