title: Point mutations in murineNkx2-5phenocopy human congenital heart disease and induce pathogenic Wnt signaling.
abstract: Mutations in theNkx2-5gene are a main cause of congenital heart disease. Several studies have addressed the phenotypic consequences of disrupting theNkx2-5gene locus, although animal models to date failed to recapitulate the full spectrum of the human disease. Here, we describe a newNkx2-5point 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 ofNkx2-5-driven pathology, a primary right ventricular dysfunction. We further describe the molecular consequences of disrupting the transcriptional network regulated byNkx2-5in the heart and show thatNkx2-5-dependent perturbation of the Wnt signaling pathway promotes heart dysfunction through alteration of cardiomyocyte metabolism. Our data provide mechanistic insights on howNkx2-5regulates 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 byNKX2-5mutations in patients.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.|Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Milena B
authors.initials: MB
authors.lastname: Furtado
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.|Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Wilmanns
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Anjana
authors.initials: A
authors.lastname: Chandran
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Joelle
authors.initials: J
authors.lastname: Perera
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Hon
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Biben
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Willow
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Hieu T
authors.initials: HT
authors.lastname: Nim
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Department of Physiology.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Simonds
authors.affiliation: Monash Biomedical Imaging, Monash University, Clayton, Australia.
authors.forename: Qizhu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Willians
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Salimova
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, Singapore.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Plachta
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Denegre
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Murray
authors.affiliation: Molecular Cardiology, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.|Faculty of Medicine and School of Biological and Biomolecular Sciences, University of New South Wales, Kensington, Australia.|Cardiology Department, St. Vincent's Hospital, Darlinghurst, Australia.
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
authors.affiliation: Department of Physiology.
authors.forename: Michael
authors.initials: M
authors.lastname: Cowley
authors.affiliation: Department of Physiology.|Monash Biomedical Imaging, Monash University, Clayton, Australia.
authors.forename: James T
authors.initials: JT
authors.lastname: Pearson
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Kaye
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Mirana
authors.initials: M
authors.lastname: Ramialison
authors.affiliation: Faculty of Medicine and School of Biological and Biomolecular Sciences, University of New South Wales, Kensington, Australia.|Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.|Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.|National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Rosenthal
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.|Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Mauro W
authors.initials: MW
authors.lastname: Costa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D053263:Gene Regulatory Networks; D006321:Heart / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D017354:Point Mutation; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; C484469:Nkx2-5 protein, mouse