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dc.contributor.authorP. Kirk, Edwinen_US
dc.contributor.authorSunde, Margareten_US
dc.contributor.authorW. Costa, Mauroen_US
dc.contributor.authorRankin, Scotten_US
dc.contributor.authorWolstein, Oriten_US
dc.contributor.authorLeticia Castro, M.en_US
dc.contributor.authorL. Butler, Tanyaen_US
dc.contributor.authorHyun, Changbaigen_US
dc.contributor.authorGuo, Guanglanen_US
dc.contributor.authorOtway, Robynen_US
dc.contributor.authorMackay, Joel P.en_US
dc.contributor.authorB. Waddell, Leighen_US
dc.contributor.authorD. Cole, Andrewen_US
dc.contributor.authorHayward, Christopheren_US
dc.contributor.authorKeogh, Anneen_US
dc.contributor.authorMacdonald, Peteren_US
dc.contributor.authorGriffiths, Lynen_US
dc.contributor.authorFatkin, Dianneen_US
dc.contributor.authorF. Sholler, Garyen_US
dc.contributor.authorM. Zorn, Aaronen_US
dc.contributor.authorP. Feneley, Michaelen_US
dc.contributor.authorS. Winlaw, Daviden_US
dc.contributor.authorP. Harvey, Richarden_US
dc.description.abstractThe 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.en_US
dc.publisherCell Pressen_US
dc.relation.ispartofjournalAmerican Journal of Human Geneticsen_US
dc.titleMutations in Cardiac T-Box Factor Gene TBX20 are associated with Diverse Cardiac Pathologies, Including Defects of Septation and Valvulogenesis and Cardiomyopathyen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.hasfulltextNo Full Text

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