Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family

Qy, Li; Newbury-Ecob, RA; Ja, Terrett; Dg, Wilson; Ar, Curtis; Ch, Yi; Gebuhr, Thomas C.; Pj, Bullen; Robson, SC; Strachan, Tom; Bonnet, Damien; Lyonnet, Stanislas; Young, I.D.; Raeburn, J. A.; Buckler, Aj; Dj, Law; Brook, David

doi:10.1038/ng0197-21

Cited by 825 publications

(146 citation statements)

References 75 publications

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“…The existence of several human congenital syndromes caused by disruption of human TBX genes, demonstrates their importance in morphogenesis. The Holt-Oram syndrome is caused by TBX5 haploinsufficiency and is characterized by heart and hand anomalies [2]. Mutations in TBX1 have been implicated in the Velocardiofacial or DiGeorge syndrome in which congenital heart defects are present [3].…”

Section: Introductionmentioning

confidence: 99%

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

et al. 2007

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BackgroundThe heart forms from a linear tube that is subject to complex remodeling during embryonic development. Hallmarks of this remodeling are the looping of the heart tube and the regionalization into chamber and non-chamber myocardium. Cardiomyocytes in the future chamber myocardium acquire different cellular and physiological characteristics through activation of a chamber-specific genetic program, which is in part mediated by T-box genes.Methodology/Principal FindingWe characterize two new zebrafish T-box transcription factors, tbx3b and tbx2a, and analyze their role during the development of the atrioventricular canal. Loss- and gain-of-function analyses demonstrate that tbx3b and tbx2a are necessary to repress the chamber-genetic program in the non-chamber myocardium. We also show that tbx3b and tbx2a are required to control cell proliferation in the atrioventricular canal and that misregulation of cell proliferation in the heart tube influences looping. Furthermore, we characterize the heart phenotype of a novel Tbx3 mutation in mice and show that both the control of cell proliferation and the repression of chamber-specific genetic program in the non-chamber myocardium are conserved roles of Tbx3 in this species.Conclusions/SignificanceTaken together, our results uncover an evolutionarily conserved role of Tbx2/3 transcription factors during remodeling of the heart myocardium and highlight the importance of controlling cell proliferation as a driving force of morphogenesis.

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Section: Introductionmentioning

confidence: 99%

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

et al. 2007

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“…TBR1 is of particular interest, because it encodes a neuron-specific transcription factor of the T-box family. T-box proteins have diverse biological roles 9 and haploinsufficiency of this class of regulatory protein has already been established as a cause of human disease 10 —for instance, ulnar-mammary syndrome and Holt–Oram syndrome are caused by haploinsufficiency of TBX3 and TBX5 , respectively 11–13 . TBR1 has established roles in patterning of the central nervous system, including regulation of neuronal identities during cortical development 14 .…”

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confidence: 99%

De novo TBR1 mutations in sporadic autism disrupt protein functions

et al. 2014

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Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.

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“…Accumulating evidence suggests that genetic factors contribute to the persistence of PFO and other defects of atrial septation, including atrial septal defects (ASD) [9], [10], [11]. A number of studies have shown that ASD exhibits autosomal dominant inheritance, and a list of causative genes encoding cardiac transcription factors and their targets ( NKX2-5 [12], TBX5 [13], GATA4 [10], MYH6 [14], ACTC [15], TBX20 [16]) have been identified. Variation in these genes or their expression may contribute to the development of PFO.…”

Section: Introductionmentioning

confidence: 99%

Foramen Ovale Closure Is a Process of Endothelial-to-Mesenchymal Transition Leading to Fibrosis

et al. 2014

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Patent foramen ovale (PFO) is an atrial septal deformity present in around 25% of the general population. PFO is associated with major causes of morbidity, including stroke and migraine. PFO appears to be heritable but genes involved in the closure of foramen ovale have not been identified. The aim of this study is to determine molecular pathways and genes that are responsible to the postnatal closure of the foramen ovale. Using Sprague-Dawley rat hearts as a model we analysed the dynamic histological changes and gene expressions at the foramen ovale region between embryonic day 20 and postnatal day 7. We observed a gradual loss of the endothelial marker PECAM1, an upregulation of the mesenchymal marker vimentin and α-smooth muscle actin, the elevation of the transcription factor Snail, and an increase of fibroblast activation protein (FAP) in the foramen ovale region as well as the deposition of collagen-rich connective tissues at the closed foramen ovale, suggesting endothelial-to-mesenchymal transition (EndMT) occurring during foramen ovale closure which leads to fibrosis. In addition, Notch1 and Notch3 receptors, Notch ligand Jagged1 and Notch effector HRT1 were highly expressed in the endocardium of the foramen ovale region during EndMT. Activation of Notch3 alone in an endothelial cell culture model was able to drive EndMT and transform endothelial cells to mesenchymal phenotype. Our data demonstrate for the first time that FO closure is a process of EndMT-mediated fibrosis, and Notch signalling is an important player participating in this process. Elucidation of the molecular mechanisms of the closure of foramen ovale informs the pathogenesis of PFO and may provide potential options for screening and prevention of PFO related conditions.

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Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family

Cited by 825 publications

References 75 publications

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

De novo TBR1 mutations in sporadic autism disrupt protein functions

Foramen Ovale Closure Is a Process of Endothelial-to-Mesenchymal Transition Leading to Fibrosis

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