Haploinsufficiency of TAB2 causes congenital heart defects in humans.
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.
Thienpont
Bernard
B
Laboratory for the Genetics of Human Development, Department of Human Genetics, University of Leuven, B3000 Leuven, Belgium.
Zhang
Litu
L
Postma
Alex V
AV
Breckpot
Jeroen
J
Tranchevent
Léon-Charles
LC
Van Loo
Peter
P
Møllgård
Kjeld
K
Tommerup
Niels
N
Bache
Iben
I
Tümer
Zeynep
Z
van Engelen
Klaartje
K
Menten
Björn
B
Mortier
Geert
G
Waggoner
Darrel
D
Gewillig
Marc
M
Moreau
Yves
Y
Devriendt
Koen
K
Larsen
Lars Allan
LA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6; D004622:Embryo, Mammalian; D005260:Female; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D014178:Translocation, Genetic; D015027:Zebrafish / Q000196:embryology
D048868:Adaptor Proteins, Signal Transducing; C410585:TAB2 protein, human