Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Surprisingly, Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50\% reduction of T-box transcription factors cause disease. Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome conduction system defects, suggest mechanisms for intrafamilial phenotypic variability, and account for related cardiac malformations caused by other transcription factor mutations.
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%0 Journal Article
%1 Bruneau.2001
%A Bruneau, B. G.
%A Nemer, G.
%A Schmitt, J. P.
%A Charron, F.
%A Robitaille, L.
%A Caron, S.
%A Conner, D. A.
%A Gessler, M.
%A Nemer, M.
%A Seidman, C. E.
%A Seidman, J. G.
%D 2001
%J Cell
%K (Genetics) Abnormalities;Multiple/*genetics Acid Aging Alignment Animals Atrial Base Binding Bone Cell Connexins/genetics Data Defects;Congenital/*genetics/physiopathology Development Development/genetics/*physiology Differentiation Disease Domain Electrocardiography Embryonic;Fetal Factor/*genetics Forelimb/abnormalities Heart Heart/embryology Heterozygote Homology;Nucleic Homozygote Humans Mice Mice;Knockout Models;Animal Molecular Myocardium/cytology Natriuretic Promoter Proteins/deficiency/*genetics Rats Regions Sequence Sheep Sites Syndrome T-Box
%N 6
%P 709--721
%T A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease
%V 106
%X Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Surprisingly, Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50\% reduction of T-box transcription factors cause disease. Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome conduction system defects, suggest mechanisms for intrafamilial phenotypic variability, and account for related cardiac malformations caused by other transcription factor mutations.
@article{Bruneau.2001,
abstract = {Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Surprisingly, Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50{\%} reduction of T-box transcription factors cause disease. Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome conduction system defects, suggest mechanisms for intrafamilial phenotypic variability, and account for related cardiac malformations caused by other transcription factor mutations.},
added-at = {2013-01-29T13:47:26.000+0100},
author = {Bruneau, B. G. and Nemer, G. and Schmitt, J. P. and Charron, F. and Robitaille, L. and Caron, S. and Conner, D. A. and Gessler, M. and Nemer, M. and Seidman, C. E. and Seidman, J. G.},
biburl = {https://www.bibsonomy.org/bibtex/2a6620354f8e62c90c28de9661ff21e12/ebch},
interhash = {052356dada9a19057443c24c40726f49},
intrahash = {a6620354f8e62c90c28de9661ff21e12},
journal = {Cell},
keywords = {(Genetics) Abnormalities;Multiple/*genetics Acid Aging Alignment Animals Atrial Base Binding Bone Cell Connexins/genetics Data Defects;Congenital/*genetics/physiopathology Development Development/genetics/*physiology Differentiation Disease Domain Electrocardiography Embryonic;Fetal Factor/*genetics Forelimb/abnormalities Heart Heart/embryology Heterozygote Homology;Nucleic Homozygote Humans Mice Mice;Knockout Models;Animal Molecular Myocardium/cytology Natriuretic Promoter Proteins/deficiency/*genetics Rats Regions Sequence Sheep Sites Syndrome T-Box},
number = 6,
pages = {709--721},
timestamp = {2013-01-29T13:47:40.000+0100},
title = {A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease},
volume = 106,
year = 2001
}