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Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling
Milena B. Furtado, … , Nadia A. Rosenthal, Mauro W. Costa
Milena B. Furtado, … , Nadia A. Rosenthal, Mauro W. Costa
Published March 23, 2017
Citation Information: JCI Insight. 2017;2(6):e88271. https://doi.org/10.1172/jci.insight.88271.
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Research Article Cardiology Development

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

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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.

Authors

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

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Figure 1

NKX2-5 mutant protein displays decreased affinity for its endogenous DNA binding sites.

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NKX2-5 mutant protein displays decreased affinity for its endogenous DNA...
In situ analysis of DNA binding in transiently transfected HL-1 cardiomyocytes confirms decreased affinity of Nkx2-5 I184M and P for target sites. (A) Example of nucleus analyzed by photoactivation; H2B-RFP fluorescence (red) colocalizes with Nk2-5-paGFP–transcfected (green) cells, while GFP can only be visualized after photoactivation. (B) Typical autocorrelation curves for paGFP and NKX2-5 proteins (WT, 183M, and 183P), showing fast and slow diffusion components for each protein. Note anomalous diffusion for NKX2-5 mutant proteins. pa, photoactivatable; RFP, red fluorescent protein; G, fluctuations in fluorescence; τ, time in milliseconds.

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