Document Detail

Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis.
MedLine Citation:
PMID:  22203979     Owner:  NLM     Status:  MEDLINE    
TBX3 is critical for human development: mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development, maturation, and maintenance of the conduction system are not well understood. We tested the requirements for Tbx3 in these processes. We generated a unique series of Tbx3 hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of Tbx3 function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias: sinus pauses and bradycardia indicate sinoatrial node dysfunction, whereas preexcitation and atrioventricular block reveal abnormalities in the atrioventricular junction. Surviving Tbx3 mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of Tbx3 in adults reveal its requirement for conduction system homeostasis. Arrhythmias in Tbx3-deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers. These findings indicate that Tbx3 is required for the conduction system to establish and maintain its correct molecular identity and functional properties. In conclusion, Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner. TBX3 and its regulatory targets merit investigation as candidates for human arrhythmias.
Deborah U Frank; Kandis L Carter; Kirk R Thomas; R Michael Burr; Martijn L Bakker; William A Coetzee; Martin Tristani-Firouzi; Michael J Bamshad; Vincent M Christoffels; Anne M Moon
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-12-27
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-03-21     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E154-63     Citation Subset:  IM    
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MeSH Terms
Animals, Newborn
Arrhythmias, Cardiac / complications,  pathology,  physiopathology*,  ultrasonography
Atrioventricular Block / complications,  pathology,  physiopathology,  ultrasonography
Atrioventricular Node / pathology,  physiopathology
Connexin 43 / metabolism
Embryo, Mammalian / abnormalities,  pathology
Gene Dosage*
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Heart Conduction System / abnormalities,  pathology,  physiopathology*,  ultrasonography
Homeostasis / genetics*
Ion Channels / genetics,  metabolism
Mutation / genetics
RNA, Messenger / genetics,  metabolism
Recombination, Genetic / genetics
Survival Analysis
T-Box Domain Proteins / deficiency*,  genetics*,  metabolism
Grant Support
K12HD047349/HD/NICHD NIH HHS; R01 HD046767/HD/NICHD NIH HHS; R01 HD046767-01A1/HD/NICHD NIH HHS; R01 HD046767-02/HD/NICHD NIH HHS; R01 HD046767-03/HD/NICHD NIH HHS; R01 HD046767-04/HD/NICHD NIH HHS; R01 HD046767-05/HD/NICHD NIH HHS; R01 HD046767-05S1/HD/NICHD NIH HHS; R01HD046767/HD/NICHD NIH HHS
Reg. No./Substance:
0/Connexin 43; 0/Ion Channels; 0/RNA, Messenger; 0/T-Box Domain Proteins; 0/Tbx3 protein, mouse

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