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 - Keywords: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Chromosome Deletion; Chromosomes, Human, Pair 6; Embryo, Mammalian; Female; Gene Knockdown Techniques; Genetic Association Studies; Heart; Heart Defects, Congenital; Humans; Male; Molecular Sequence Data; Mutation; Pedigree; Translocation, Genetic; Zebrafish
PY - 2010
Y1 - 2010
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-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.
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-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.
U2 - 10.1016/j.ajhg.2010.04.011
DO - 10.1016/j.ajhg.2010.04.011
M3 - Journal 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 -