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Published on: December 2, 2014
Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling
Milena B Furtado1,2, Julia C Wilmanns2,3, Anjana Chandran2
1The Jackson Laboratory, Bar Harbor, Maine, USA.
Abstract:
Mutations in the Nkx2-5 gene are a main cause of congenital heart disease. Several studies have addressed the phenotypic consequences of disrupting the Nkx2-5 gene locus, although animal models to date failed to recapitulate the full spectrum of the human disease. Here, we describe a new Nkx2-5 point mutation murine model, akin to its human counterpart disease-generating mutation. Our model fully reproduces the morphological and physiological clinical presentations of the disease and reveals an understudied aspect of Nkx2-5-driven pathology, a primary right ventricular dysfunction. We further describe the molecular consequences of disrupting the transcriptional network regulated by Nkx2-5 in the heart and show that Nkx2-5-dependent perturbation of the Wnt signaling pathway promotes heart dysfunction through alteration of cardiomyocyte metabolism. Our data provide mechanistic insights on how Nkx2-5 regulates heart function and metabolism, a link in the study of congenital heart disease, and confirms that our models are the first murine genetic models to our knowledge to present all spectra of clinically relevant adult congenital heart disease phenotypes generated by NKX2-5 mutations in patients.
Insights
A new mouse model with an Nkx2-5 gene mutation fully replicates congenital heart disease, revealing right ventricular dysfunction and metabolic changes. This model offers crucial insights into Nkx2-5
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- Mutations in the Nkx2-5 gene are a primary cause of congenital heart disease (CHD).
- Existing animal models have not fully replicated the spectrum of human Nkx2-5-related CHD phenotypes.
- Understanding Nkx2-5's role is critical for developing effective treatments for CHD.
Purpose of the Study:
- To develop and characterize a novel murine model of Nkx2-5 mutation-induced CHD.
- To investigate the full spectrum of morphological and physiological consequences of Nkx2-5 disruption.
- To elucidate the molecular mechanisms underlying Nkx2-5-driven cardiac pathology, including right ventricular dysfunction and metabolic alterations.
Main Methods:
- Generation of a point mutation Nkx2-5 murine model mimicking human disease-causing mutations.
- Comprehensive morphological and physiological characterization of the murine model.
- Analysis of the molecular consequences, including transcriptional network disruption and Wnt signaling pathway perturbation.
- Investigation of cardiomyocyte metabolism alterations.
Main Results:
- The novel murine model accurately recapitulates the clinical presentations of human Nkx2-5-related CHD.
- Primary right ventricular dysfunction was identified as a key, understudied aspect of Nkx2-5 pathology.
- Disruption of the Nkx2-5 transcriptional network perturbs the Wnt signaling pathway, impacting cardiomyocyte metabolism and leading to heart dysfunction.
- This model presents the complete spectrum of clinically relevant adult CHD phenotypes associated with Nkx2-5 mutations.
Conclusions:
- The developed Nkx2-5 point mutation murine model is a valuable tool for studying congenital heart disease.
- Nkx2-5 plays a critical role in regulating heart function and metabolism, with implications for Wnt signaling.
- This research provides mechanistic insights into Nkx2-5-driven pathology and offers a comprehensive model for adult CHD phenotypes.
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