Novel TBX3 mutation data in families with Ulnar–Mammary syndrome indicate a genotype–phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects

Meneghini, Vasco; Odent, Sylvie; Platonova, N.; Egeo, Aliana; Merlo, Giorgio R.

doi:10.1016/j.ejmg.2005.04.021

Cited by 63 publications

(51 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 Interestingly, ventricular septal defects and pulmonary stenosis were observed in one UMS family, suggesting that this phenotype may be part of this syndrome, albeit with low penetrance, indicating that the occurrence depends on other mutations or genetic background. 19 Conduction system defects have not been reported in UMS patients, and our findings indicate that heterozygous Tbx3 mutant mice do not have obvious structural heart defects or conduction system defects. These observations indicate that Tbx3 levels in heterozygous mutants are sufficient for the formation of the conduction system, ventricular septum, and outflow tract.…”

Section: Discussionmentioning

confidence: 68%

“…16,17 Mutations in Tbx3 cause ulnarmammary syndrome (UMS) in humans, a congenital disorder associated with defects in limbs, mammary glands, teeth and, occasionally, the heart. 18,19 In the heart, Tbx3 is specifically expressed in the conduction system. 20 Recently, we have found that Tbx3 acts as a molecular switch that determines whether embryonic cardiac cells differentiate into pacemaker cells or working myocardium.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Bakker

Boukens

Mommersteeg

et al. 2008

Circulation Research

179

182

View full text Add to dashboard Cite

Abstract-The cardiac conduction system consists of distinctive heart muscle cells that initiate and propagate the electric impulse required for coordinated contraction. The conduction system expresses the transcriptional repressor Tbx3, which is required for vertebrate development and controls the formation of the sinus node. In humans, mutations in Tbx3 cause ulnar-mammary syndrome. Here, we investigated the role of Tbx3 in the molecular specification of the atrioventricular conduction system. Expression analysis revealed early delineation of the atrioventricular bundle and proximal bundle branches by Tbx3 expression in human, mouse, and chicken. Tbx3-deficient mice, which die between embryonic day 12.5 and 15.5, ectopically expressed genes for connexin (Cx)43, atrial natriuretic factor (Nppa), Tbx18, and Tbx20 in the atrioventricular bundle and proximal bundle branches. Cx40 was precociously upregulated in the atrioventricular bundle of Tbx3 mutants. Moreover, the atrioventricular bundle and branches failed to exit the cell cycle in Tbx3 mutant embryos. Finally, Tbx3-deficient embryos developed outflow tract malformations and ventricular septal defects. These data reveal that Tbx3 is required for the molecular specification of the atrioventricular bundle and bundle branches and for the development of the ventricular septum and outflow tract. Our data suggest a mechanism in which Tbx3 represses differentiation into ventricular working myocardium, thereby imposing the conduction system phenotype on cells within its expression domain. Key Words: Tbx3 Ⅲ conduction system Ⅲ atrioventricular bundle Ⅲ bundle branches Ⅲ development T he cardiac conduction system is responsible for the initiation, coordination, and propagation of the electric impulse. The impulse is initiated in the sinus node, delayed in the atrioventricular (AV) node, and then rapidly propagated by the AV bundle (bundle of His), bundle branches, and the peripheral conduction system to activate the ventricular working myocardium from apex to base. Disorders of the conduction system, including sinus node dysfunction and AV block, occur commonly and may cause life-threatening arrhythmias requiring pacemaker implantation or treatment with antiarrhythmic medication. Congenital heart defects and gene mutations significantly contribute to conduction system disorders. [1][2][3] Since the anatomic identification of the conduction system components 100 years ago, knowledge regarding their development, morphology, and physiological function has increased steadily. 4 -10 However, insight into the molecular and genetic underpinnings of the specification and formation of the conduction system is very limited. Human and mouse studies have identified cardiac homeobox factor Nkx2-5, T-box transcription factor Tbx5, Id2, and bone morphogenetic protein signaling as important molecular components for the formation of the AV conduction system [11][12][13][14][15] and Tbx3 as a critical factor in the formation of the sinus node. 14 Tbx3 is a T-box transcription factor in...

show abstract

Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 99%

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Bakker

Boukens

Mommersteeg

et al. 2008

Circulation Research

179

182

View full text Add to dashboard Cite

show abstract

“…Mutations in TBX3 cause human ulnar-mammary syndrome (UMS), characterized by limb malformations, apocrine and mammary gland hypoplasia, and dental and genital abnormalities (8). Cardiac structural defects have been reported in two patients with UMS, one with the Wolff-Parkinson-White syndrome conduction abnormality (7,9). TBX3 expression was decreased in the hearts of patients with right ventricular outflow tract tachycardia, and variability in the TBX5-TBX3 region correlates with PR interval duration (10,11).…”

mentioning

confidence: 99%

Lethal arrhythmias in Tbx3 -deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis

Frank¹,

Carter²,

Thomas

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

126

138

View full text Add to dashboard Cite

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.heart rhythm | heart development | embryonic electrocardiogram | tissue regeneration

show abstract

“…Tbx3 is a transcriptional repressor involved in developmental patterning and the regulation of proliferation, senescence bypass, and apoptosis in a variety of tissues (He et al 1999;Brummelkamp et al 2002;Carlson et al 2002;Davenport et al 2003;Naiche et al 2005). Mutations in TBX3 cause human ulnar-mammary syndrome, a disorder characterized by abnormal development of forelimbs, apocrine glands, teeth, and, occasionally, the heart (Bamshad et al 1997;Meneghini et al 2006). Because of its unique nodal expression pattern in the heart and functional equivalence to Tbx2, a potent repressor of markers for working myocardial differentiation including Nppa, Smpx, and Cx40 in the developing heart (Habets et al 2002;Christoffels et al 2004b;Harrelson et al 2004), Tbx3 is an attractive candidate regulator for the SAN gene program.…”

mentioning

confidence: 99%

Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria

Hoogaars¹,

Engel²,

Brons³

et al. 2007

Genes Dev.

367

413

View full text Add to dashboard Cite

The sinoatrial node initiates the heartbeat and controls the rate and rhythm of contraction, thus serving as the pacemaker of the heart. Despite the crucial role of the sinoatrial node in heart function, the mechanisms that underlie its specification and formation are not known. Tbx3, a transcriptional repressor required for development of vertebrates, is expressed in the developing conduction system. Here we show that Tbx3 expression delineates the sinoatrial node region, which runs a gene expression program that is distinct from that of the bordering atrial cells. We found lineage segregation of Tbx3-negative atrial and Tbx3-positive sinoatrial node precursor cells as soon as cardiac cells turn on the atrial gene expression program. Tbx3 deficiency resulted in expansion of expression of the atrial gene program into the sinoatrial node domain, and partial loss of sinoatrial node-specific gene expression. Ectopic expression of Tbx3 in mice revealed that Tbx3 represses the atrial phenotype and imposes the pacemaker phenotype on the atria. The mice displayed arrhythmias and developed functional ectopic pacemakers. These data identify a Tbx3-dependent pathway for the specification and formation of the sinoatrial node, and show that Tbx3 regulates the pacemaker gene expression program and phenotype.[Keywords: Heart development; pacemaker; sinoatrial node; lineage; Tbx3; transgenic mice] Supplemental material is available at http://www.genesdev.org.

show abstract

Novel TBX3 mutation data in families with Ulnar–Mammary syndrome indicate a genotype–phenotype relationship: mutations that do not disrupt the T-domain are associated with less severe limb defects

Cited by 63 publications

References 17 publications

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Lethal arrhythmias in Tbx3 -deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis

Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria

Contact Info

Product

Resources

About