Transgenic Mouse Model of Ventricular Preexcitation and Atrioventricular Reentrant Tachycardia Induced by an AMP-Activated Protein Kinase Loss-of-Function Mutation Responsible for Wolff-Parkinson-White Syndrome

Sidhu, Jasvinder; Rajawat, Yadavendra S.; Rami, Tapan G.; Gollob, Michael H.; Wang, Zhinong; Yuan, Ruiyong; Marian, Ali J.; DeMayo, Francesco J.; Weilbacher, Donald E.; Taffet, George E.; Davies, James; Carling, David; Khoury, Dirar S.; Roberts, Robert J.

doi:10.1161/01.cir.0000151291.32974.d5

Cited by 136 publications

(150 citation statements)

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“…Homologous with yeast Snf1, AMPK is activated classically by an increased ratio of AMP to ATP, resulting in activation of energy-producing pathways and suppression of energy-consuming ones to restore ATP levels; AMPK also is controlled by an AMP-independent osmotic stress pathway (13). A distinguishing feature of preexcitation caused by PRKAG2 mutations is glycogen accumulation (7)(8)(9)14), with fatal congenital cardiac glycogenosis in the most severe example (15). Several of the human mutations confer a loss of function in culture (16,17), and at least two result in diminished AMPK activity in vivo (9,14), but increased basal activity also is observed (7,8,15).…”

mentioning

confidence: 99%

A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway

Xie¹,

Zhang²,

Dyck

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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322

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TGF-␤-activated kinase-1 (TAK1), also known as MAPKK kinase-7 (MAP3K7), is a candidate effector of multiple circuits in cardiac biology and disease. Here, we show that inhibition of TAK1 in mice by a cardiac-specific dominant-negative mutation evokes electrophysiological and biochemical properties reminiscent of human Wolff-Parkinson-White syndrome, arising from mutations in AMPactivated protein kinase (AMPK), most notably, accelerated atrioventricular conduction and impaired AMPK activation. To test conclusively the biochemical connection from TAK1 to AMPK suggested by this phenotype, we disrupted TAK1 in mouse embryos and embryonic fibroblasts by Cre-mediated recombination. In TAK1-null embryos, the activating phosphorylation of AMPK at T172 was blocked, accompanied by defective AMPK activity. However, loss of endogenous TAK1 causes midgestation lethality, with defective yolk sac and intraembryonic vasculature. To preclude confounding lethal defects, we acutely ablated floxed TAK1 in culture by viral delivery of Cre. In culture, endogenous TAK1 was activated by oligomycin, the antidiabetic drug metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR), and ischemia, well established triggers of AMPK activity. Loss of TAK1 in culture blocked T172 phosphorylation induced by all three agents, interfered with AMPK activation, impaired phosphorylation of the endogenous AMPK substrate acetyl CoA carboxylase, and also interfered with activation of the AMPK kinase LKB1. Thus, by disrupting the endogenous TAK1 locus, we prove a pivotal role for TAK1 in the LKB1͞AMPK signaling axis, an essential governor of cell metabolism. APKs, MAPKKs (MAP2Ks), and MAP2K kinases (MAP3Ks) comprise a multitiered signaling cascade that couples extracellular cues and intracellular stresses to diverse effector pathways controlling cell growth, survival, transcription, and function (1). Among upstream members of this superfamily, TGF-␤-activated kinase-1 (TAK1)͞MA PKK kinase-7 (MAP3K7) first was identified as a mammalian kinase that complements the lack of Ste11, a MAP3K, in yeast and is activated by TGF-␤ and the relative, bone morphogenetic protein (2). Within the MAPK family, TAK1 is coupled preferentially to JNK and p38. Additional inputs for TAK1 activation include cytokine signaling and innate immunity, and additional outputs include I B kinase ␤ (3). Disruption of TAK1 by saturation mutagenesis in ES cells substantiated that TAK1 is indeed essential for a subset of TGF-␤ effects and also exerts essential functions in signaling by cytokine and Toll-like receptors (3), as proposed on earlier grounds. Additionally, the early-lethal phenotype of TAK1-null embryos, with intraembryonic and yolk sac vascular patterning defects, resembles that of mice devoid of other TGF-␤ signaling proteins, the type I receptor Alk1 and type III receptor endoglin (4).A recognized limitation of germ-line deletions is that potential gene functions may be obscured by early lethality, indirect effects, or secondary adaptations, fueling interest in lineagerestr...

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mentioning

confidence: 99%

A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway

Xie¹,

Zhang²,

Dyck

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

322

244

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“…In addition, a modest increase in AMPKβ2 protein level and a dramatic decrease in AMPKα phosphorylation level were observed in the heart of +/H530R mice ( Figure 3F), which were also observed in transgenic mice (Supplementary information, Figure S1A and S1F). These phenotypes resembled those of mice carrying R302Q mutation in PRKAG2 [9,34], and were greatly reversed following Cas9/sgRNA-m3 injection. We also detected reduced AMPKγ2 protein level in +/H530R mice injected with Cas9/sgRNA-m3 relative to those with EGFP ( Figure 3F, compare lanes 7-9 with lanes 4-6).…”

Section: Crispr/cas9-mediated Genome Editing Rescued Prk-ag2 Cardiac mentioning

confidence: 80%

“…Transgenic mouse models have been widely used to validate the mutations causing PRKAG2 cardiac syndrome [5,9,27,28]. To investigate whether the H530R mutation accounts for the disease, we generated transgenic mice expressing WT (Tg-WT) and H530R (Tg-H530R) forms of PRKAG2 under the control of heart-specific α-myosin heavy chain (αMHC) promoter ( Figure 1E).…”

Section: H530r Mutation Results In Prkag2 Cardiac Syndromementioning

confidence: 99%

“…Although these mutations result in similar phenotypes including glycogen storage, cardiac hypertrophy and ventricular pre-excitation, their influences on cardiac AMPK activity are distinct [5,7,9,36]. For example, the N488I and R531Q mutations constitutively increase AMPK activity [5,7].…”

Section: Discussionmentioning

confidence: 99%

“…With a prevalence of 0.1%-0.3%, WPW syndrome accounts for about 10.5% of sudden cardiac deaths in individuals younger than 35-years old [1,2]. WPW patients usually exhibit cardiomyopathy characterized by ventricular pre-excitation, progressive conduction system disease and cardiac hypertrophy [3][4][5][6][7][8][9], followed later by fatal ventricular tachyarrhythmia and progressive heart failure refractory to medical treatment, leaving patients with cardiac transplantation as the only hope.…”

Section: Introductionmentioning

confidence: 99%

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Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome

et al. 2016

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PRKAG2 cardiac syndrome is an autosomal dominant inherited disease resulted from mutations in the PRK-AG2 gene that encodes γ2 regulatory subunit of AMP-activated protein kinase. Affected patients usually develop ventricular tachyarrhythmia and experience progressive heart failure that is refractory to medical treatment and requires cardiac transplantation. In this study, we identify a H530R mutation in PRKAG2 from patients with familial Wolff-Parkinson-White syndrome. By generating H530R PRKAG2 transgenic and knock-in mice, we show that both models recapitulate human symptoms including cardiac hypertrophy and glycogen storage, confirming that the H530R mutation is causally related to PRKAG2 cardiac syndrome. We further combine adeno-associated virus-9 (AAV9) and the CRISPR/Cas9 gene-editing system to disrupt the mutant PRKAG2 allele encoding H530R while leaving the wild-type allele intact. A single systemic injection of AAV9-Cas9/sgRNA at postnatal day 4 or day 42 substantially restores the morphology and function of the heart in H530R PRKAG2 transgenic and knock-in mice. Together, our work suggests that in vivo CRISPR/Cas9 genome editing is an effective tool in the treatment of PRKAG2 cardiac syndrome and other dominant inherited cardiac diseases by selectively disrupting disease-causing mutations.

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Molecular Genetics of Cardiovascular Disorders

Marian

Roberts

2009

Evidence‐Based Cardiology

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Transgenic Mouse Model of Ventricular Preexcitation and Atrioventricular Reentrant Tachycardia Induced by an AMP-Activated Protein Kinase Loss-of-Function Mutation Responsible for Wolff-Parkinson-White Syndrome

Abstract: Background-We identified a gene (PRKAG2) that encodes the ␥-2 regulatory subunit of AMP-activated protein kinase (AMPK) with a mutation (Arg302Gln)

Cited by 136 publications

References 26 publications

A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway

A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway

Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome

Molecular Genetics of Cardiovascular Disorders

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