| First Author | Furtado MB | Year | 2017 |
| Journal | JCI Insight | Volume | 2 |
| Issue | 6 | Pages | e88271 |
| PubMed ID | 28352650 | Mgi Jnum | J:239808 |
| Mgi Id | MGI:5829780 | Doi | 10.1172/jci.insight.88271 |
| Citation | Furtado MB, et al. (2017) Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling. JCI Insight 2(6):e88271 |
| abstractText | 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. |
