Haploinsufficiency of TAB2 causes congenital heart defects in humans

Bernard Thienpont; Litu Zhang; Alex V Postma; Jeroen Breckpot; Léon-Charles Tranchevent; Peter Van Loo; Kjeld Møllgård; Niels Tommerup; Iben Bache; Zeynep Tümer; Klaartje van Engelen; Björn Menten; Geert Mortier; Darrel Waggoner; Marc Gewillig; Yves Moreau; Koen Devriendt; Lars Allan Larsen

doi:10.1016/j.ajhg.2010.04.011

Haploinsufficiency of TAB2 causes congenital heart defects in humans

Bernard Thienpont, Litu Zhang, Alex V Postma, Jeroen Breckpot, Léon-Charles Tranchevent, Peter Van Loo, Kjeld Møllgård, Niels Tommerup, Iben Bache, Zeynep Tümer, Klaartje van Engelen, Björn Menten, Geert Mortier, Darrel Waggoner, Marc Gewillig, Yves Moreau, Koen Devriendt, Lars Allan Larsen

Department of Cellular and Molecular Medicine

57 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Human Genetics
Volume	86
Issue number	6
Pages (from-to)	839-49
Number of pages	10
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2010.04.011
Publication status	Published - 11 Jul 2010

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Thienpont, B., Zhang, L., Postma, A. V., Breckpot, J., Tranchevent, L.-C., Van Loo, P., Møllgård, K., Tommerup, N., Bache, I., Tümer, Z., van Engelen, K., Menten, B., Mortier, G., Waggoner, D., Gewillig, M., Moreau, Y., Devriendt, K., & Larsen, L. A. (2010). Haploinsufficiency of TAB2 causes congenital heart defects in humans. American Journal of Human Genetics, 86(6), 839-49. https://doi.org/10.1016/j.ajhg.2010.04.011

Thienpont, B, Zhang, L, Postma, AV, Breckpot, J, Tranchevent, L-C, Van Loo, P, Møllgård, K , Tommerup, N , Bache, I , Tümer, Z, van Engelen, K, Menten, B, Mortier, G, Waggoner, D, Gewillig, M, Moreau, Y, Devriendt, K & Larsen, LA 2010, 'Haploinsufficiency of TAB2 causes congenital heart defects in humans', American Journal of Human Genetics, vol. 86, no. 6, pp. 839-49. https://doi.org/10.1016/j.ajhg.2010.04.011

@article{b8ed52708ff311df928f000ea68e967b,

title = "Haploinsufficiency of TAB2 causes congenital heart defects in humans",

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.",

author = "Bernard Thienpont and Litu Zhang and Postma, {Alex V} and Jeroen Breckpot and L{\'e}on-Charles Tranchevent and {Van Loo}, Peter and Kjeld M{\o}llg{\aa}rd and Niels Tommerup and Iben Bache and Zeynep T{\"u}mer and {van Engelen}, Klaartje and Bj{\"o}rn Menten and Geert Mortier and Darrel Waggoner and Marc Gewillig and Yves Moreau and Koen Devriendt and Larsen, {Lars Allan}",

note = "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",

year = "2010",

month = jul,

day = "11",

doi = "10.1016/j.ajhg.2010.04.011",

language = "English",

volume = "86",

pages = "839--49",

journal = "American Journal of Human Genetics",

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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 - 2010/7/11

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.

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 -

Haploinsufficiency of TAB2 causes congenital heart defects in humans

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