TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy

Zhao, Cuimei; Bing-Sun,; Song, Haoming; Wang, Juan; Xu, Wenjun; Jiang, Jianzhong; Qiu, Xing‐Biao; Fang, Yuan; Xu, Jiahong; Yang, Yi‐Qing

doi:10.1515/cclm-2015-0328

Cited by 41 publications

(25 citation statements)

References 45 publications

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“…It has been verified that NKX2-5 can interact physically with other cardiac core transcriptional factors to form complexes, including GATA4 and TBX20 with profiles of expression and function in the heart overlapping with those of NKX2-5, and regulate synergistically the expression of multiple critical cardiac genes, including those coding for ANF, CX40, and Ca 2+ channels. 28,30,36,37) In this study, the NKX2-5 mutations identified in the patients with sporadic adult-onset DCM and congenital ASD were shown to result in significantly diminished transcriptional activation of the ANF promoter alone or in synergy with GATA4 or TBX20, suggesting that haplo-insufficiency or dominant-negative effect caused by the NKX2-5 mutations is potentially an alternative pathological mechanism of DCM as well as ASD and AVB.…”

Section: Discussionmentioning

confidence: 66%

“…8,[10][11][12][13][14][15][16][17][18][19][20] Although we made a genetic analysis of several cardiac core transcriptional factor genes in the two mutation carriers with DCM, including GATA4, GATA5, GATA6, TBX5, TBX20, and HAND1, as described previously, [22][23][24][25][26][27][28][29][30][31] and found no mutations, we cannot rule out the possibility that the genetic variants in other genes may also contribute to DCM in these two patients. Genome sequencing analysis may help to explain the possibility for these patients.…”

Section: Discussionmentioning

confidence: 90%

“…Notably, NKX2-5 physically interacts with such cooperative partners as GATA4, TBX5, and TBX20, and has been shown to cooperatively regulate the transcription of several essential cardiac target genes, such as troponin I, troponin C, α-actin, and α-myosin heavy chain, 37) and furthermore, mutations in these cooperative partners and cardiac target genes have been causally related to DCM. 8,22,23,[26][27][28][29][30] Hence, it is likely that genetically compromised NKX2-5 confers increased susceptibility to DCM by down-regulating expressions of cardiac target genes.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24][25][26][27][28][29][30][31] More interestingly, mutations in NKX2-5, another cardiac key transcriptional factor, have been found to be responsible for familial adult-onset DCM, 32,33) which makes it justifiable to evaluate the prevalence and spectrum of NKX2-5 mutations in the patients with sporadic adult-onset DCM.…”

Section: Ilated Cardiomyopathy (Dcm) Which Is Defined Bymentioning

confidence: 99%

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Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Guo

et al. 2017

Int. Heart J.

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SummaryDilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients. (Int Heart J 2017; 58: 521-529)

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Ilated Cardiomyopathy (Dcm) Which Is Defined Bymentioning

confidence: 99%

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Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Guo

et al. 2017

Int. Heart J.

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“…Although the genetic basis underpinning a number of these defects remains to be elucidated, the core cardiac transcription factors, which are expressed predominantly in the heart and mediate the expression of genes encoding cardiac structural proteins or regulatory proteins, are increasingly recognized as being important in the normal development of the heart (6). Mutations in certain genes encoding core cardiac transcription factors, including homeodomain-containing NK2 homeobox 5 (NKX2.5) and NKX2.6 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), GATA-binding protein (GATA) 4, GATA5 and GATA6 (17)(18)(19)(20)(21)(22)(23)(24), T-box protein (TBX) 5 and TBX20 (25)(26)(27)(28)(29), and a paired-like homeobox transcription factor, PITX2 (30-33), have emerged as major contributors to several types of congenital heart defects (2,5,6,34).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block

Qiu

Fang

et al. 2017

Molecular Medicine Reports

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Congenital atrial septal defect (ASD) and progressive atriventricular block (AVB) are the two most common phenotypes linked to NK2 homeobox 5 (NKX2.5) mutations in animals and humans. However, the prevalence and spectrum of NKX2.5 mutation in patients with ASD and AVB remain to be elucidated. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeobox‑containing transcription factor essential for development of the heart, were sequenced in a cohort of 62 unrelated patients with ASD and AVB, and subsequently in a mutation carrier's available family members. As controls, 300 unrelated, ethnically‑matched healthy individuals were recruited, who were also genotyped for NKX2.5. The functional consequence of the mutant NKX2.5 was evaluated in contrast to its wild‑type counterpart using a dual‑luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.Q181X, was identified in an index patient with ASD and AVB, with a prevalence of ~1.61%. Genetic analysis of the proband's pedigree revealed that the mutation co‑segregated with ASD and AVB with complete penetrance. The nonsense mutation, which eliminated partial homeobox and the carboxyl terminus, was absent in the 600 control chromosomes. Functional evaluation showed that the NKX2.5 mutant had no transcriptional activity. Furthermore, the mutation disrupted the synergistic activation between NKX2.5 and GATA binding protein 4, another cardiac core transcription factor associated with ASD. The results of the present study expand the spectrum of NKX2.5 mutations linked to ASD and AVB, and indicated that NKX2.5 loss‑of‑function mutations are an uncommon cause of ASD and AVB in humans.

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HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot

Wang

Guo

et al. 2016

Pediatr Cardiol

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As the most prevalent form of birth defect in humans worldwide, congenital heart disease (CHD) is responsible for substantial morbidity and is still the leading cause of birth defect-related demises. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD, and mutations in multiple genes, especially in those coding for cardiac core transcription factors, have been causally linked to various CHDs. Nevertheless, CHD is a genetically heterogeneous disease and the genetic determinants underpinning CHD in an overwhelming majority of patients remain elusive. In the current study, genomic DNA was extracted from venous blood samples of 165 unrelated patients with CHD, and the coding exons and splicing junction sites of the HAND1 gene, which encodes a basic helix-loop-helix transcription factor essential for cardiovascular development, were sequenced. As a result, a novel heterozygous mutation, p.R118C, was identified in a patient with tetralogy of Fallot (TOF). The missense mutation, which was absent in 600 referential chromosomes, altered the amino acid that was completely conserved evolutionarily. Biological assays with a dual-luciferase reporter assay system revealed that the R118C-mutant HAND1 protein had significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation of a downstream target gene between HAND1 and GATA4, another cardiac core transcription factor associated with TOF. To our knowledge, this is the first report on the association of a HAND1 loss-of-function mutation with enhanced susceptibility to TOF in humans. The findings provide novel insight into the molecular etiology underlying TOF, suggesting potential implications for the improved prophylactic and therapeutic strategies for TOF.

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TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy

Abstract: This study links TBX20 loss-of-function mutation to idiopathic DCM in humans for the first time, providing novel insight into the molecular mechanism underpinning DCM.

Cited by 41 publications

References 45 publications

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block

HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot

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