A novel de novo<i>TBX5</i>mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function

Dreßen, Martina; Lahm, Harald; Lahm, Armin; Wolf, Klaudia; Doppler, S.; Deutsch, Marcus-André; Cleuziou, Julie; Ohain, Jelena Pabst von; Schön, Patrick; Ewert, Peter; Malčić, Ivan; Lange, Rüdiger; Krane, Markus

doi:10.1002/mgg3.234

Cited by 18 publications

(13 citation statements)

References 45 publications

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“…Twenty-four hours later, cells were transiently transfected with pCMV-SPORT6-TBX5 (1.0 μg/well) or pCMV-SPORT6-TBX5 mutant (R264K and P85T) (1.0 μg/well), and pGL3-vector (1.5 μg/well) or the pGL3-ANF promoter reporter (1.5 μg/well) vectors using TransIT-293 transfection reagent (Mirus, WI, USA). A previously reported TBX5 P85T mutant was included in the transactivation study as a positive control [18]. A β-galactosidase control vector (the RSV LTR/β-galactosidase plasmid DNA) (50 ng) was used as an internal control.…”

Section: Analysis Of Transcriptional Activity By Luciferase Assaymentioning

confidence: 99%

TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway

et al. 2020

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Background TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also been identified in a few cardiomyopathy patients and considered causative. We identified a TBX5 variant (c.791G>A, p.Arg264Lys), that is over-represented in cardiomyopathy patients. This variant is located outside of the T-box domain, and its pathogenicity has not been confirmed by functional analyses. Objective To investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy. Methods and results We developed mice expressing Tbx5 R264K. Mice homozygous for this variant displayed compensated dilated cardiomyopathy; mild decreased fractional shortening, dilatation of the left ventricle, left ventricular wall thinning and increased heart weight without major heart structural disorders. There was no difference in activation of the ANF promotor, a transcriptional target of Tbx5, compared to wild-type. However, analysis of RNA isolated from left ventricular samples showed significant increases in the expression of Acta1 in left ventricle with concomitant increases in the protein level of ACTA1.

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Section: Analysis Of Transcriptional Activity By Luciferase Assaymentioning

confidence: 99%

TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway

et al. 2020

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“…To date, numerous HOS-related mutations of the TBX5 gene have been reported in humans (56). Recently, a new mutation in the DNA binding domain of TBX5 (p.Pro85Thr) that leads to a conformational change in protein structure has been described by our group (57). Interestingly, upon mutation or a dose reduction of the TBX5 gene, transgenic mice (58) and zebrafish (24) display a HOS-like phenotype, suggesting conserved function of the transcription factor TBX5 throughout vertebrate evolution.…”

Section: Hosmentioning

confidence: 99%

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

et al. 2017

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Congenital heart disease (CHD) is the leading cause of infant death, affecting approximately 4-14 live births per 1,000. Although surgical techniques and interventions have improved significantly, a large number of infants still face poor clinical outcomes. MicroRNAs (miRs) are known to coordinately regulate cardiac development and stimulate pathological processes in the heart, including fibrosis or hypertrophy and impair angiogenesis. Dysregulation of these regulators could therefore contribute (I) to the initial development of CHD and (II) at least partially to the observed clinical outcomes of many CHD patients by stimulating the aforementioned pathways. Thus, miRs may exhibit great potential as therapeutic targets in regenerative medicine. In this review we provide an overview of miR function and elucidate their role in selected CHDs, including hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TOF), ventricular septal defects (VSDs) and Holt-Oram syndrome (HOS). We then bridge this knowledge to the potential usefulness of miRs and/or their targets in therapeutic strategies for regenerative purposes in CHDs.

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“…TBX5 transcription factor is an essential regulator in cardiac development [105] as it plays a role in gastrulation process and organogenesis in vertebrates [106]. TBX5 mutation is common in patients with Holt-Oram syndrome, a syndrome which is characterized by skeletal abnormalities and heart diseases [54,107,108]. TBX5 mutations were found in patients with tetralogy of Fallot associated with large ostium secundum defect and features of upper limb deformities [109], and also in patients with the ventricular septal defects [110].…”

Section: Embryogenesis Of the Heartmentioning

confidence: 99%

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

Suluba

Liu

Xia

et al. 2020

Egypt J Med Hum Genet

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Background: Congenital heart diseases (CHDs) are the most common congenital anomalies with an estimated prevalence of 8 in 1000 live births. CHDs occur as a result of abnormal embryogenesis of the heart. Congenital heart diseases are associated with significant mortality and morbidity. The damage of the heart is irreversible due to a lack of regeneration potential, and usually, the patients may require surgical intervention. Studying the developmental biology of the heart is essential not only in understanding the mechanisms and pathogenesis of congenital heart diseases but also in providing us with insight towards developing new preventive and treatment methods. Main body: The etiology of congenital heart diseases is still elusive. Both genetic and environmental factors have been implicated to play a role in the pathogenesis of the diseases. Recently, cardiac transcription factors, cardiacspecific genes, and signaling pathways, which are responsible for early cardiac morphogenesis have been extensively studied in both human and animal experiments but leave much to be desired. The discovery of novel genetic methods such as next generation sequencing and chromosomal microarrays have led to further study the genes, non-coding RNAs and subtle chromosomal changes, elucidating their implications to the etiology of congenital heart diseases. Studies have also implicated non-hereditary risk factors such as rubella infection, teratogens, maternal age, diabetes mellitus, and abnormal hemodynamics in causing CHDs. These etiological factors raise questions on multifactorial etiology of CHDs. It is therefore important to endeavor in research based on finding the causes of CHDs. Finding causative factors will enable us to plan intervention strategies and mitigate the consequences associated with CHDs. This review, therefore, puts forward the genetic and non-genetic causes of congenital heart diseases. Besides, it discusses crucial signaling pathways which are involved in early cardiac morphogenesis. Consequently, we aim to consolidate our knowledge on multifactorial causes of CHDs so as to pave a way for further research regarding CHDs. Conclusion: The multifactorial etiology of congenital heart diseases gives us a challenge to explicitly establishing specific causative factors and therefore plan intervention strategies. More well-designed studies and the use of novel genetic technologies could be the way through the discovery of etiological factors implicated in the pathogenesis of congenital heart diseases.

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A novel de novoTBX5mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function

Cited by 18 publications

References 45 publications

TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway

TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways

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