A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

Jiang, Weifeng; Xu, Ying‐Jia; Zhao, Cuimei; Wang, Xinhua; Qiu, Xing‐Biao; Liu, Xu; Wu, Shaohui; Yang, Yi‐Qing

doi:10.1590/1678-4685-gmb-2020-0142

Cited by 11 publications

(9 citation statements)

References 89 publications

(98 reference statements)

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“…Functional investigations demonstrated that the Glu144*-mutant KLF13 failed to transcriptionally activate the promoters of NPPA and VEGFA . Additionally, the mutation abrogated the synergistic transcriptional activation between KLF13 and TBX5, a well-established CHD-causative gene ( 68 , 69 , 84 ). These findings support the fact that genetically defective KLF13 confers an enhanced susceptibility to CHD, including PDA, BAV and VSD.…”

Section: Discussionmentioning

confidence: 99%

“…PCR products were resolved by 1.5% agarose gel electrophoresis and visualized after ethidium bromide staining of gels. PCR-sequencing of extracted amplicons was conducted as described previously ( 69 ). For a validated KLF13 variation, the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/ac/index.php ), Single Nucleotide Polymorphism (SNP) datbase ( https://www.ncbi.nlm.nih.gov/snp ) and the Genome Aggregation Database (gnomAD; https://gnomad.broadinstitute.org ) were retrieved to verify its novelty.…”

Section: Methodsmentioning

confidence: 99%

“…A total of 400 unrelated volunteers without CHD were enrolled as control individuals from the same geographic area, who were exactly matched with the cases for sex and ethnicity, as well as age. All research participants underwent a comprehensive clinical assessment, as described previously (67)(68)(69). This research was fulfilled in compliance with the tenets of the Declaration of Helsinki.…”

Section: Recruitment and Clinical Evaluation Of Study Participantsmentioning

confidence: 99%

Section: Genetic Analysis Of Klf13mentioning

confidence: 99%

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A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve

et al. 2022

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Recently, mutations in the Kruppel-like factor 13 (KLF13) gene encoding a Kruppel-like transcription factor have been reported to cause congenital heart disease (CHD). However, due to pronounced genetic heterogeneity, the mutational spectrum of KLF13 in other cohorts of cases suffering from distinct types of CHD remain to be ascertained. In the present investigation, by Sanger sequencing of KLF13 in 316 unrelated cases affected by different forms of CHD, a new mutation in heterozygous status, NM_015995.3: c.430G>T; p.(Glu144*), was detected in an index patient affected with patent ductus arteriosus (PDA) and ventricular septal defect (VSD), as well as bicuspid aortic valve (BAV), with a mutation frequency of ~0.32%. Genetic investigation of the available family members of the proband demonstrated that the truncating mutation co-segregated with CHD. The nonsense mutation was not observed in 400 unrelated volunteers without CHD who were enrolled as control subjects. Quantitative biological measurements with dual luciferase reporters revealed that Glu144*-mutant KLF13 did not transactivate the downstream genes vascular endothelial growth factor A and natriuretic peptide A. In addition, the mutation abrogated the synergistic transcriptional activation between KLF13 and T-box transcription factor 5, a well-established CHD-causing gene. In conclusion, the present study indicates that genetically defective KLF13 contributes to familial PDA and VSD, as well as BAV, which expands the phenotypic spectrum linked to KLF13, and reveals a novel molecular pathogenesis of the disease, providing a new molecular target for the early prophylaxis and individualized treatment of CHD.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Recruitment and Clinical Evaluation Of Study Participantsmentioning

confidence: 99%

Section: Genetic Analysis Of Klf13mentioning

confidence: 99%

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A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve

et al. 2022

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“…This gene, previously associated with atrial fibrillation, was sequenced in unrelated adult patients suffering from both congenital heart defects and atrial fibrillation. A novel nonsense mutation that impairs the transcriptional activity of the protein was found segregating also with BAV in the family [ 40 ]. This finding highlights the importance of deciphering the molecular pathways implicated in order to identify new candidate genes for genetic studies.…”

Section: Genetics Insights Into Bicuspid Aortopathymentioning

confidence: 99%

Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy

Junco-Vicente

Río-García

Martı́n

et al. 2021

IJMS

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Bicuspid aortic valve (BAV) associated with aortopathy is the most common congenital heart disease in the general population. Far from being a simple harmless valve malformation, it can be a complex and heterogeneous disease and a source of chronic and acute pathology (early valvular disease, aneurysm, dissection). In the previous years, intense research has been carried out to find out and understand its mechanisms, but the pathophysiology of the disease is still not fully understood and many questions remain open. Recent studies have discovered several genetic mutations involved in the development of valvular and aortic malformations, but still cannot explain more than 5–10% of cases. Other studies have also focused on molecular alterations and cellular processes (TGF-β pathway, microRNAs, degradation of the extracellular matrix, metalloproteinases, etc.), being a field in constant search and development, looking for a therapeutic target to prevent the development of the disease. Increased knowledge about this multifaceted disorder, derived from both basic and clinical research, may influence the diagnosis, follow-up, prognosis, and therapies of affected patients in the near future. This review focuses on the latest and outstanding developments on the molecular and genetic investigations of the bicuspid aortopathy.

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Comparison of Outcome in Patients With Familial Versus Spontaneous Atrial Septal Defect

Nielsen

Ellesøe

Larsen

et al. 2022

The American Journal of Cardiology

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A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

Cited by 11 publications

References 89 publications

A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve

A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve

Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy

Comparison of Outcome in Patients With Familial Versus Spontaneous Atrial Septal Defect

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