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

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 & 4 others Mirana Ramialison, Richard P. Harvey, Nadia A. Rosenthal, Mauro W. Costa

Research output: Contribution to journalArticleResearch

4 Citations (Scopus)

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.

Original languageEnglish
Article numbere88271
Pages (from-to)e88271
Number of pages18
JournalJCI Insight
Volume2
Issue number6
DOIs
Publication statusPublished - 23 Mar 2017

Cite this

Furtado, Milena B. ; Wilmanns, Julia C. ; Chandran, Anjana ; Perera, Joelle ; Hon, Olivia ; Biben, Christine ; Willow, Taylor J. ; Nim, Hieu T. ; Kaur, Gurpreet ; Simonds, Stephanie ; Wu, Qizhu ; Willians, David ; Salimova, Ekaterina ; Plachta, Nicolas ; Denegre, James M. ; Murray, Stephen A. ; Fatkin, Diane ; Cowley, Michael ; Pearson, James T. ; Kaye, David ; Ramialison, Mirana ; Harvey, Richard P. ; Rosenthal, Nadia A. ; Costa, Mauro W. / Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling. In: JCI Insight. 2017 ; Vol. 2, No. 6. pp. e88271.
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title = "Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling",
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.",
author = "Furtado, {Milena B.} and Wilmanns, {Julia C.} and Anjana Chandran and Joelle Perera and Olivia Hon and Christine Biben and Willow, {Taylor J.} and Nim, {Hieu T.} and Gurpreet Kaur and Stephanie Simonds and Qizhu Wu and David Willians and Ekaterina Salimova and Nicolas Plachta and Denegre, {James M.} and Murray, {Stephen A.} and Diane Fatkin and Michael Cowley and Pearson, {James T.} and David Kaye and Mirana Ramialison and Harvey, {Richard P.} and Rosenthal, {Nadia A.} and Costa, {Mauro W.}",
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doi = "10.1172/jci.insight.88271",
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Furtado, MB, Wilmanns, JC, Chandran, A, Perera, J, Hon, O, Biben, C, Willow, TJ, Nim, HT, Kaur, G, Simonds, S, Wu, Q, Willians, D, Salimova, E, Plachta, N, Denegre, JM, Murray, SA, Fatkin, D, Cowley, M, Pearson, JT, Kaye, D, Ramialison, M, Harvey, RP, Rosenthal, NA & Costa, MW 2017, 'Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling', JCI Insight, vol. 2, no. 6, e88271, pp. e88271. https://doi.org/10.1172/jci.insight.88271

Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling. / Furtado, Milena B.; Wilmanns, Julia C.; Chandran, Anjana; Perera, Joelle; Hon, Olivia; Biben, Christine; Willow, Taylor J.; Nim, Hieu T.; Kaur, Gurpreet; Simonds, Stephanie; Wu, Qizhu; Willians, David; Salimova, Ekaterina; Plachta, Nicolas; Denegre, James M.; Murray, Stephen A.; Fatkin, Diane; Cowley, Michael; Pearson, James T.; Kaye, David; Ramialison, Mirana; Harvey, Richard P.; Rosenthal, Nadia A.; Costa, Mauro W.

In: JCI Insight, Vol. 2, No. 6, e88271, 23.03.2017, p. e88271.

Research output: Contribution to journalArticleResearch

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T1 - Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling

AU - Furtado, Milena B.

AU - Wilmanns, Julia C.

AU - Chandran, Anjana

AU - Perera, Joelle

AU - Hon, Olivia

AU - Biben, Christine

AU - Willow, Taylor J.

AU - Nim, Hieu T.

AU - Kaur, Gurpreet

AU - Simonds, Stephanie

AU - Wu, Qizhu

AU - Willians, David

AU - Salimova, Ekaterina

AU - Plachta, Nicolas

AU - Denegre, James M.

AU - Murray, Stephen A.

AU - Fatkin, Diane

AU - Cowley, Michael

AU - Pearson, James T.

AU - Kaye, David

AU - Ramialison, Mirana

AU - Harvey, Richard P.

AU - Rosenthal, Nadia A.

AU - Costa, Mauro W.

PY - 2017/3/23

Y1 - 2017/3/23

N2 - 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.

AB - 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.

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DO - 10.1172/jci.insight.88271

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