Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling

Furtado, Milena B.; Wilmanns, Julia C.; Chandran, Anjana; Perera, J. Kishan; Hon, Olivia J.; Biben, Christine; Willow, Taylor J.; Nim, Hieu T.; Kaur, Gurpreet; Simonds, Stephanie E.; Wu, Qisong; Willians, David; Salimova, Ekaterina; Plachta, Nicolas; Denegre, James M.; Murray, Stephen A.; Fatkin, Diane; Cowley, Michael A.; Pearson, James T.; Kaye, David M.; Ramialison, Mirana; Harvey, Richard P.; Rosenthal, Nadia; Costa, Mauro W.

doi:10.1172/jci.insight.88271

Cited by 23 publications

(29 citation statements)

References 71 publications

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“…Our immunohistological analysis revealed upregulated Six1 expression in endothelial cells and cardiomyocytes of the trabecular zone, suggesting that deregulation of this gene is associated with cardiac pathology rather than being a direct target of Nkx2-5. Interestingly, Six1 has been recently found to be deregulated in cardiomyopathy induced by Nkx2-5 point mutation or in human patients [ 56 , 57 ]. Our data suggest that Six1 may be a good marker for pathological forms of excessive trabeculation in non-compaction cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

et al. 2018

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Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.

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Section: Discussionmentioning

confidence: 99%

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

et al. 2018

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“…Nkx2-5 C/+ and Nkx2-5 183P/+ (ACHD) heterozygous mice have been previously characterized [9]. All mice were maintained on a C57BL/6J background, housed at Monash Animal Services, Australia, or at The Jackson Laboratory, USA.…”

Section: Methodsmentioning

confidence: 99%

“…Despite the existence of large epidemiological datasets, not much is currently known about how ACHD predisposes patients to heart failure upon metabolic stress. The present study focuses on how obesity affects cardiac function in our recently characterized ACHD model [8], [9]. Using genetically predisposed mice [9] and diet as a cardiac stressor, we describe a preexistent imbalance in the metabolic state of ACHD hearts.…”

Section: Introductionmentioning

confidence: 99%

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Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease

Wilmanns

Pandey

Hon

et al. 2019

Molecular Metabolism

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ObjectiveCongenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.MethodsWe used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model.ResultsACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice.ConclusionsThis study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospect for a translational reassessment of ACHD presentation in the clinic.

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“…Inherited mutations of the Nkx2-5 gene are a common genetic cause of CHD in humans as they can result in an assortment of cardiac malformations, such as right isomerism, atrioventricular (AV) block, ventricular septal defect (VSD), and atrial septal defect (ASD) (5)(6)(7)(8)(9). Over 50 Nkx2-5 mutations have been identified that result in congenital heart defects, many of which have been represented in mutant mouse models (6,(10)(11)(12). We have previously developed a heterozygous knock-in mutant mouse model with missense mutation 52Arg→Gly (R52G) in the Nkx2-5 transcription factor homeodomain (13).…”

Section: Introductionmentioning

confidence: 99%

Extracellular Matrix Disparities in an Nkx2-5 Mutant Mouse Model of Congenital Heart Disease

Bousalis

Lacko

Hlavac

et al. 2020

Front. Cardiovasc. Med.

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Congenital heart disease (CHD) affects almost one percent of all live births. Despite diagnostic and surgical reparative advances, the causes and mechanisms of CHD are still primarily unknown. The extracellular matrix plays a large role in cell communication, function, and differentiation, and therefore likely plays a role in disease development and pathophysiology. Cell adhesion and gap junction proteins, such as integrins and connexins, are also essential to cellular communication and behavior, and could interact directly (integrins) or indirectly (connexins) with the extracellular matrix. In this work, we explore disparities in the expression and spatial patterning of extracellular matrix, adhesion, and gap junction proteins between wild type and Nkx2-5 +/R52G mutant mice. Decellularization and proteomic analysis, Western blotting, histology, immunostaining, and mechanical assessment of embryonic and neonatal wild type and Nkx2-5 mutant mouse hearts were performed. An increased abundance of collagen IV, fibronectin, and integrin β-1 was found in Nkx2-5 mutant neonatal mouse hearts, as well as increased expression of connexin 43 in embryonic mutant hearts. Furthermore, a ventricular noncompaction phenotype was observed in both embryonic and neonatal mutant hearts, as well as spatial disorganization of ECM proteins collagen IV and laminin in mutant hearts. Characterizing such properties in a mutant mouse model provides valuable information that can be applied to better understanding the mechanisms of congenital heart disease.

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Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling

Cited by 23 publications

References 71 publications

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease

Extracellular Matrix Disparities in an Nkx2-5 Mutant Mouse Model of Congenital Heart Disease

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