BioProject

Mutations in Nkx2-5 are a main cause of cardiac congenital heart disease. Here we describe a new Nkx2-5 point-mutation murine model, akin to its human counterpart disease generating mutation. More...

Mutations in Nkx2-5 are a main cause of cardiac congenital heart 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 under-studied 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 novel link in the study of congenital heart disease, and confirms that our models are the first murine genetic models to present all spectra of clinically relevant congenital heart disease phenotypes generated by Nkx2-5 mutations in patients. Overall design: Comparative trancriptional profile of adult heart samples from knockin mouse knockin models containing full deletion of Nkx2-5 or I183M or I183P substitution when compared to control lines where I was changed to I at position 183 (keeping WT gene) Less...