Journal article

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 Show all

JCI INSIGHT | AMER SOC CLINICAL INVESTIGATION INC | Published : 2017

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..

View full abstract

University of Melbourne Researchers

Grants

Awarded by NHMRC


Awarded by NHMRC/NHF


Awarded by NATIONAL CANCER INSTITUTE


Funding Acknowledgements

We acknowledge the use of Monash University MicroImaging, Monash Biomedical Imaging, and Monash Gene Targeting Facilities. We would also like to thanks Peter Williams for help with mitochondrial data analysis. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. This work was also funded by NHMRC-Australia Fellowship to NAR and NHMRC Project grant 1069710 to MWC and NAR, NHMRC/NHF 1049980 CDF to MR, and ARC Stem Cells Australia to NAR. NHMRC Project grants 025008 and 1074386 and The Estate of the Late RT Hall to DF. HTN is supported by the Richard Pratt Fellowship in Prostate Cancer.