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Haploinsufficiency of TAB2 Causes Congenital Heart Defects in Humans |
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| Authors: | Bernard Thienpont Litu Zhang Alex V Postma Léon-Charles Tranchevent Kjeld Møllgård Iben Bache Klaartje van Engelen Geert Mortier Darrel Waggoner Yves Moreau Lars Allan Larsen |
| Institution: | 1 Laboratory for the Genetics of Human Development, Department of Human Genetics, University of Leuven, B3000 Leuven, Belgium 2 Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark 3 Department of Anatomy & Embryology, Heart Failure Research Center, L2-108-2, Academic Medical Center Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands 4 Department of Electrical Engineering ESAT-SCD, University of Leuven, B3000 Leuven, Belgium 5 Department of Human Genetics, University of Leuven, B3000 Leuven, Belgium 6 Department of Molecular and Developmental Genetics, VIB, B3000 Leuven, Belgium 7 Developmental Biology Unit, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark 8 Applied Human Molecular Genetics, Kennedy Center, DK-2600 Glostrup, Denmark 9 Department of Cardiology and Clinical Genetics, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands 10 Center for Medical Genetics, Ghent University Hospital, B9000 Ghent, Belgium 11 Department of Medical Genetics, Antwerp University and Antwerp University Hospital, B2160 Antwerpen, Belgium 12 Department of Pediatrics and Department of Genetics of the University of Chicago, Chicago, IL 60637, USA 13 Paediatric Cardiology Unit, University Hospitals Leuven, B3000 Leuven, Belgium |
| 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-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. |
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