Mutations in Cardiac T-Box Factor Gene TBX20 are associated with Diverse Cardiac Pathologies, Including Defects of Septation and Valvulogenesis and Cardiomyopathy

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Title Mutations in Cardiac T-Box Factor Gene TBX20 are associated with Diverse Cardiac Pathologies, Including Defects of Septation and Valvulogenesis and Cardiomyopathy
Author Kirk, Edwin P.; Sunde, Margaret; Costa, Mauro W.; Rankin, Scott A; Wolstein, Orit; Castro, M. Leticia; Butler, Tanya L.; Hyun, Changbaig; Guo, Guanglan; Otway, Robyn; Mackay, Joel P.; Waddell, Leigh B.; Cole, Andrew D.; Hayward, Christopher; Keogh, Anne; Macdonald, Peter; Griffiths, Lyn; Fatkin, Dianne; Sholler, Gary F.; Zorn, Aaron M.; Feneley, Michael P.; Winlaw, David S.; Harvey, Richard P.
Journal Name American Journal of Human Genetics
Year Published 2007
Place of publication USA
Publisher Cell Press
Abstract The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference–mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2- 5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.
Peer Reviewed Yes
Published Yes
Volume 81
Issue Number 2
Page from 280
Page to 291
ISSN 0002-9297
Date Accessioned 2008-02-29
Date Available 2008-04-18T07:09:04Z
Language en_AU
Research Centre Griffith Health Institute; Molecular Basis of Disease
Faculty Griffith Health Faculty
Subject Gene Expression
URI http://hdl.handle.net/10072/17764
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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