Identification of a Gene Responsible for Familial Wolff–Parkinson–White Syndrome

Gollob, MH; Green, Manfred S.; As, Tang; Gollob, Tanya N.; Karibe, Akihiko; As, Ali Hassan; Ahmad, Ferhaan; Lozado, Ryan J.; Shah, Grishma; Fananapazir, Lameh; Ll, Bachinski; Roberts, Robert J.

doi:10.1056/nejm200106143442403

Cited by 593 publications

(272 citation statements)

References 21 publications

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“…Although there have been no comparable studies in humans, given the close similarity between the rat and human AMPK complexes, it seems likely that this will also be the case in humans. Combined with the observation that mutations in ␥ 2 are inherited in a dominant manner (11,12), these findings indicate that a relatively small reduction in total AMPK activity within the cell can lead to a severe pathophysiological condition. Taken together with the knowledge that the ␥ 2 mutations cause a cardiac-specific defect, and do not cause detectable abnormalities in other tissues, these characteristics indicate that ␥ 2 -containing AMPK complexes must play a unique role in heart development, which cannot be compensated for by the other ␥ isoforms.…”

Section: Discussionmentioning

confidence: 91%

“…These mutations were first identified in individuals with abnormal cardiac function, including pre-excitation (Wolff-Parkinson-White syndrome) and hypertrophy (11)(12)(13). None of the mutations caused constitutive activation of AMPK as judged either by direct measurement of activity or by the phosphorylation state of Thr 172 .…”

Section: Discussionmentioning

confidence: 99%

“…Several groups have reported recently the identification of six different mutations in the ␥2 subunit from patients with cardiac hypertrophy and associated electrophysiologic abnormalties (11)(12)(13)(14). All six mutations result in amino acid substitutions and are located within the C-terminal half of the protein.…”

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confidence: 99%

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Functional Analysis of Mutations in the γ2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome

Daniel

Carling

2002

Journal of Biological Chemistry

110

100

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Mutations in the gene encoding the ␥ 2 subunit of the AMP-activated protein kinase (AMPK) have recently been shown to cause cardiac hypertrophy and ventricular pre-excitation (Wolff-Parkinson-White syndrome). We have examined the effect of four of these mutations on AMPK activity. The mutant ␥ 2 polypeptides are all able to form functional complexes following co-expression with either ␣ 1 ␤ 1 or ␣ 2 ␤ 1 in mammalian cells. None of the mutations caused any detectable change in the phosphorylation of threonine 172 within the ␣ subunit of AMPK. Consequently, in the absence of an appropriate stimulus the mutant complexes, like the wild-type complex, exist in an inactive form demonstrating that the mutations do not lead to constitutive activation of the kinase. Three of the mutations we studied occur within the cystathionine ␤-synthase (CBS) domains of ␥ 2 . Two of these mutations lead to a marked decrease in AMP dependence, whereas the third reduces AMP sensitivity. These findings suggest that the CBS domains play an important role in AMP-binding within the complex. In contrast, a fourth mutation, which lies between adjacent CBS domains, has no significant effect on AMPK activity in vitro. These results indicate that mutations in ␥ 2 have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms.The AMP-activated protein kinase (AMPK) 1 is the central component of a protein kinase cascade that plays a pivotal role in the regulation of energy metabolism (1). In response to activation following an increase in the AMP/ATP ratio, AMPK phosphorylates a number of downstream targets culminating in the switching off of energy (ATP)-utilizing pathways and the switching on of energy-generating pathways (1, 2). Activation of AMPK is complex and involves direct allosteric activation of the enzyme by AMP as well as phosphorylation, catalyzed by an upstream kinase, AMPK kinase (AMPKK) (3, 4). AMPK is a heterotrimeric complex, consisting of a catalytic subunit (␣) and two regulatory subunits (␤ and ␥) (5, 6) and isoforms of all three subunits have been identified (7-9). Although there is compelling evidence indicating that formation of the heterotrimeric complex is necessary for significant kinase activity (6, 10) the precise role of the regulatory subunits remains unclear. In addition, at present our understanding of the physiological relevance of the different subunit isoforms is very limited.Several groups have reported recently the identification of six different mutations in the ␥2 subunit from patients with cardiac hypertrophy and associated electrophysiologic abnormalties (11-14). All six mutations result in amino acid substitutions and are located within the C-terminal half of the protein. The mutations lead to the development of aberrant conduction systems, including pre-excitation, characteristic of Wolff-Parkinson-White syndrome (15) and in all but one case, the mutations also result in severe cardiac hypertrophy. No evidence of cardiac hypertro...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Functional Analysis of Mutations in the γ2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome

Daniel

Carling

2002

Journal of Biological Chemistry

110

100

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“…The latter components are consistent with suggested functions of TAK1 in growth factor signaling for AV cushion development (19), defects in which can cause preexcitation (20). However, given the existence of AMPK mutations in humans as a genetic basis for preexcitation (6)(7)(8)(9), the electrophysiological phenotype prompted us to test for glycogen accumulation and altered AMPK activation, potential signatures of abnormalities in the AMPK pathway.…”

Section: Dominant-negative Tak1 (Dntak1) Prevents the Activating Phosmentioning

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.

319

244

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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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“…The first identification of a ␥ subunit mutation was the substitution R200Q in ␥3 of pig, which increases glycogen levels in skeletal muscle (21). In humans, mutations in the ␥2 subunit cause cardiac hypertrophy, glycogen accumulation, and ventricular pre-excitation associated with Wolff-Parkinson-White syndrome (19,(22)(23)(24)(25)(26). Such mutations decrease the affinity of the ␥ subunit for AMP and ATP, reduce allosteric AMP activation, and despite some controversy, appear to increase the basal phosphorylation and activity of AMPK in cells expressing LKB1 (18, 19, 26 -28).…”

mentioning

confidence: 99%

Roles of the Glycogen-binding Domain and Snf4 in Glucose Inhibition of SNF1 Protein Kinase

Momcilovic

Iram

Liu

et al. 2008

Journal of Biological Chemistry

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The SNF1/AMP-activated protein kinase (AMPK) family is required for adaptation to metabolic stress and energy homeostasis. The ␥ subunit of AMPK binds AMP and ATP, and mutations that affect binding cause human disease. We have here addressed the role of the Snf4 (␥) subunit in regulating SNF1 protein kinase in response to glucose availability in Saccharomyces cerevisiae. Previous studies of mutant cells lacking Snf4 suggested that Snf4 counteracts autoinhibition by the C-terminal sequence of the Snf1 catalytic subunit but is dispensable for glucose regulation, and AMP does not activate SNF1 in vitro. We first introduced substitutions at sites that, in AMPK, contribute to nucleotide binding and regulation. Mutations at several sites relieved glucose inhibition of SNF1, as judged by catalytic activity, phosphorylation of the activation-loop Thr-210, and growth assays, although analogs of the severe human mutations R531G/Q had little effect. We further showed that alterations of Snf4 residues that interact with the glycogen-binding domain (GBD) of the ␤ subunit strongly relieved glucose inhibition. Finally, substitutions in the GBD of the Gal83 ␤ subunit that are predicted to disrupt interactions with Snf4 and also complete deletion of the GBD similarly relieved glucose inhibition of SNF1. Analysis of mutant cells lacking glycogen synthase showed that regulation of SNF1 is normal in the absence of glycogen. These findings reveal novel roles for Snf4 and the GBD in regulation of SNF1.

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Identification of a Gene Responsible for Familial Wolff–Parkinson–White Syndrome

Cited by 593 publications

References 21 publications

Functional Analysis of Mutations in the γ2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome

Functional Analysis of Mutations in the γ2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome

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

Roles of the Glycogen-binding Domain and Snf4 in Glucose Inhibition of SNF1 Protein Kinase

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