Angeborene Herzfehlbildungen von Septen, Endokardkissen und Konotrunkus

The Nkx2-5 gene codes for a transcription factor that plays a critical role in heart development. Heterozygous mutations in NKX2-5 in both human and mice result in congenital heart defects (CHDs). However, the molecular mechanisms by which these mutations cause the disease are still unknown. Recently, we have generated the heterozygous mouse model of the human CHDs associated mutation NKX2-5 R142C (Nkx2-5 mouse ortholog of human NKX2-5 R142C variant) that developed septal and conduction defects. This study generated a heterozygous Nkx2-5 R141C mouse embryonic stem cell line (Nkx2-5 mESCs) to model CHDs in vitro. We observed that Nkx2-5 mESCs display an alteration in the expression of genes that are essential for normal heart development. Furthermore, the reduced cardiomyogenesis is paralleled by a reduction in nuclear import of Nkx2-5 protein. Examination of the Nkx2-5 embryos at E8.5 revealed a transient loss of cardiomyogenesis, which is consistent with the phenotype observed in vitro. Moreover, gene expression profiling of Nkx2-5 cells at an early stage of cardiac differentiation revealed pronounced deregulation of several cardiac differentiation and function genes. Collectively, our data showed that heterozygosity for the R141C mutation results in disruption of the cellular distribution of Nkx2-5 protein, a transient reduction in cardiomyogenesis that may disrupt the early patterning of the heart, and this, in turn, affects the intricate orchestration of signaling pathways leading to downregulation of Bone morphogenetic protein (BMP) and Notch signaling. Therefore, we have developed mESCs model of a human CHD, providing an in vitro system to examine early stages of heart development, which are otherwise difficult to study in vivo. Stem Cells 2018;36:514-526.

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In Vitro Modeling of Congenital Heart Defects Associated with an NKX2-5 Mutation Revealed a Dysregulation in BMP/Notch-Mediated Signaling

Zakariyah

Rajgara

Horner

et al. 2018

Stem Cells

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Identification of ZFPM2 mutations in sporadic conotruncal heart defect patients

Tian

Liu

et al. 2017

Mol Genet Genomics

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Conotruncal heart defects (CTDs) are a group of cardiac malformations that involve outflow tract anomalies and the arterial pole of the heart. Recent reports have identified mutations in a number of genes associated with CTDs in human and animal models. ZFPM2 plays a role in cardiac development by acting as a transcriptional cofactor that interacts with GATA4. Because ZFPM2 was found to be important for cardiac development in a knockout mouse model, we screened for ZFPM2 mutations in 528 CTD patients. We identified six rare and nonsynonymous ZFPM2 variants, and this was the first time that five of these variants (R698Q, R736L, E1005K, T32A, and I488V) were reported in East Asians. Western blots showed that there was no significant difference in the protein expression of wild-type ZFPM2, ZFPM2R698Q, or ZFPM2R736L. A dual luciferase reporter assay demonstrated that both ZFPM2 mutants R698Q and R736L reduced GATA4-mediated transcription. However, when ZFPM2R698Q was co-transfected with GATA4, BNP promoter activity increased significantly, whereas co-transfection with ZFPM2R736L and GATA4 did not significantly increase BNP promoter activity. This suggests that the R698Q mutation may affect the ability of ZFPM2 to bind GATA4.

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Identification of novel significant variants of ZFPM2/FOG2 in non-syndromic tetralogy of fallot and double outlet right ventricle in a Chinese Han population

et al. 2014

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Tetralogy of Fallot (TOF) and double outlet right ventricle (DORV) are two common subtypes of conotruncal defects. Recent reports have implicated mutations in the zinc finger protein, FOG family member 2 (ZFPM2/FOG2) as a cause of TOF/DORV, but no current literature focuses on the relationship between ZFPM2/FOG2 gene and non-syndromic TOF and DORV in Chinese Han population. The purpose of this study was to estimate the occurrence and the prevalence of ZFPM2/FOG2 genetic variants in Chinese Han population with non-syndromic TOF and DORV and to investigate genotype-phenotype correlations in individuals with ZFPM2/FOG2 mutations. The whole exons of ZFPM2/FOG2 were sequenced in 98 non-syndromic TOF/DORV patients and 200 control subjects. All the six variants (G2482A, G1552A, A2107C, C452T, C3239T, C1208G) changed the amino acid (p.Val828Met, p.Ala518Thr, p.Met703Leu, p.Thr151Ile, p.Ser1080Phe, p.Ala403Gly), in which four variants (G2482A, C452T, G1552A, C3239T) were not reported before and absent in control subjects. Further analysis revealed that only occurrences of variants G2482A and A2107C had statistical significance compared to the control group (P < 0.05). In conclusion, our results provide strong evidence regarding the susceptibility of the ZFPM2 gene to the development of non-syndromic TOF/DORV. It suggests that ZFPM2/FOG2 genetic variants may be a novel potential bio-markers and treatment targets for the non-syndromic TOF and DORV.

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Angeborene Herzfehlbildungen von Septen, Endokardkissen und Konotrunkus

Cited by 4 publications

References 20 publications

In Vitro Modeling of Congenital Heart Defects Associated with an NKX2-5 Mutation Revealed a Dysregulation in BMP/Notch-Mediated Signaling

In Vitro Modeling of Congenital Heart Defects Associated with an NKX2-5 Mutation Revealed a Dysregulation in BMP/Notch-Mediated Signaling

Identification of ZFPM2 mutations in sporadic conotruncal heart defect patients

Identification of novel significant variants of ZFPM2/FOG2 in non-syndromic tetralogy of fallot and double outlet right ventricle in a Chinese Han population

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