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.