NKX2.5mutations in patients with congenital heart disease

McElhinney, Doff B.; Geiger, Elizabeth A.; Blinder, Joshua J.; Benson, D. Woodrow; Goldmuntz, Elizabeth

doi:10.1016/j.jacc.2003.05.004

Cited by 339 publications

(80 citation statements)

References 25 publications

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“…These results are consistent with a previous mouse study demonstrating that the Nkx2-5-Hand1 transcriptional pathway plays an essential role in left ventricular formation during cardiogenesis [24]. Of particular note, potential NKX2-5 mutations were found in patients with HLHS [25], [26] and a frameshift mutation in HAND1 was reported [27]. The epigenetic signature of NKX2-5 transcripts in iPS cells during differentiation is unknown [28].…”

Section: Discussionsupporting

confidence: 92%

Directed Differentiation of Patient-Specific Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 in Hypoplastic Left Heart Syndrome

et al. 2014

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The genetic basis of hypoplastic left heart syndrome (HLHS) remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS) cells. Cardiac progenitor cells (CPCs) were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS- and biventricle (BV) heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS- and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex transcriptional and epigenetic mechanisms, at least in part, through combinatorial expression of NKX2-5, HAND1, and NOTCH1 that coordinately contribute to cardiac malformations in HLHS.

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Section: Discussionsupporting

confidence: 92%

Directed Differentiation of Patient-Specific Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 in Hypoplastic Left Heart Syndrome

et al. 2014

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“…While the majority of research on the function of Nkx2-5 is focused on its role and regulation in heart formation and in congenital heart disease 32–35 , studies of Nkx2-5 function in mice additionally detected a role in extraembryonic development. Homozygous knockout of Nkx2-5 in mice resulted in deficient amniotic sac blood vessel formation, and poor contact between PECAM positive endothelial cells and the apposing mesodermal and endodermal layers.…”

Section: Introductionmentioning

confidence: 99%

Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia

Rivers

Horton

Hawk³

et al. 2014

Hypertension in Pregnancy

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Objective Preeclampsia (PE) affects 2–8% of pregnancies worldwide and is a significant source of maternal and neonatal morbidity and mortality. However, the mechanisms underlying PE are poorly understood and major questions regarding etiology and risk factors remain to be addressed. Our objective was to examine whether abnormal expression of the cardiovascular developmental transcription factor, Nkx2-5, was associated with early onset and severe pre-eclampsia (EOSPE). Methods Using qPCR and immunohistochemical assay, we examined expression of Nkx2-5 and target gene expression in EOSPE and control placental tissue. We tested resulting mechanistic hypotheses in cultured cells using shRNA knockdown, qPCR and western blot. Results Nkx2-5 is highly expressed in racially disparate fashion (Caucasians > African Americans) in a subset of early EOSPE placentae. Nkx2-5 mRNA expression is highly correlated (Caucasians > African Americans) to mRNA expression of the preeclampsia marker sFlt-1, and of the Nkx2-5 target and RNA splicing factor, Sam68. Knockdown of Sam68 expression in cultured cells significantly impacts sFlt-1 mRNA isoform generation in vitro, supporting a mechanistic hypothesis that Nkx2-5 impacts EOSPE severity in a subset of patients via upregulation of Sam68 to increase sFlt-1 expression. Expression of additional Nkx2-5 targets potentially regulating metabolic stress response is also elevated in racially disparate fashion in EOSPE. Conclusions Expression of Nkx2-5 and its target genes may directly influence the genesis and racially disparate severity, and define a mechanistically distinct subclass of EOSPE.

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“…NKX2.5 gene does this by regulating the expression of several ion channel genes and controlling atrial septal formation [17,18]. Among vertebrates, NKX2.5 is the most highly conserved gene and subject to transcriptional control via a complex series of cis-regulatory elements [19]. Because cardiac transcription factors are dosage-sensitive regulators during embryonic morphogenesis, haploinsufficiency in NKX2.5 , due to a loss of functional mutations is associated with atrioventricular conduction defects and tetralogy of Fallot [20].…”

Section: Discussionmentioning

confidence: 99%

Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease

et al. 2018

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Background and objective: Congenital heart disease (CHD) is the most common birth abnormality in the structure or function of the heart that affects approximately 1% of all newborns. Despite its prevalence and clinical importance, the etiology of CHD remains mainly unknown. Somatic and germline mutations in cardiac specific transcription factor genes have been identified as the factors responsible for various forms of CHD, particularly ventricular septal defects (VSDs), tetralogy of Fallot (TOF), and atrial septal defects (ASDs). p. NKX2.5 is a homeodomain protein that controls many of the physiological processes in cardiac development including specification and proliferation of cardiac precursors. The aim of our study was to evaluate the NKX2.5 gene mutations in sporadic pediatric patients with clinical diagnosis of congenital heart malformations. Materials and methods: In this study, we investigated mutations of the NKX2.5 gene’s coding region in 105 Iranian pediatric patients with non-familial CHD by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) and direct sequencing. Results: We observed a total of four mutations, of which, two were novel DNA sequence variants in the coding region of exon 1 (c. 95 A > T and c. 93 A > T) and two others were previously reported as single-nucleotide polymorphisms (SNPs), namely rs72554028 (c. 2357 G > A) and rs3729753 (c. 606 G > C) in exon 2. Further, observed mutations are completely absent in normal healthy individuals (n = 92). Conclusion: These results suggest that NKX2.5 mutations are highly rare in CHD patients. However, in silico analysis proves that c.95 A > T missense mutation in NKX2.5 gene is probably pathogenic and may be contributing to the risk of sporadic CHD in the Iranian population.

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NKX2.5mutations in patients with congenital heart disease

Cited by 339 publications

References 25 publications

Directed Differentiation of Patient-Specific Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 in Hypoplastic Left Heart Syndrome

Directed Differentiation of Patient-Specific Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 in Hypoplastic Left Heart Syndrome

Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia

Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease

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