Cantú Syndrome Resulting from Activating Mutation in the<i>KCNJ8</i>Gene

Cooper, Paige; Reutter, Heiko; Woelfle, Joachim; Engels, Hartmut; Grange, Dorothy K.; Haaften, Gijs van; Bon, Bregje W.M. van; Hoischen, Alexander; Nichols, Colin G.

doi:10.1002/humu.22555

Cited by 97 publications

(121 citation statements)

References 29 publications

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“…CS can arise from GOF in either Kir6.1 or SUR2 proteins of the cardiovascular K ATP channel (2)(3)(4)(5). A distinct CS cardiac pathology is characterized by high output state with enhanced cardiac contractility and enhanced chamber volume, associated with decreased vascular pulse wave velocity and low BP.…”

Section: Feedback Control Via L-type Ca Current In Compensated Cardiacmentioning

confidence: 99%

“…KATP | transgenic | cardiovascular system | KCNJ8 | Kir6.1 C antu syndrome (CS), characterized by hypertrichosis, osteochondrodysplasia, and multiple cardiovascular abnormalities (1), is caused by gain-of-function (GOF) mutations in the genes encoding the pore-forming (Kir6.1, KCNJ8) and regulatory (SUR2, ABCC9) subunits of the predominantly cardiovascular isoforms of the K ATP channel (2)(3)(4)(5). Because the same disease features arise from mutations in either of these subunits, it is concluded that CS arises from increased K ATP channel activity, as opposed to any nonelectrophysiologic function of either subunit.…”

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confidence: 99%

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K _ATP channel gain-of-function leads to increased myocardial L-type Ca ²⁺ current and contractility in Cantu syndrome

Levin

Singh

Zhang

et al. 2016

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

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Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) K ATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca 2+ current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascularspecific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in K ATP GOF models is paralleled by changes in phosphorylation of the pore-forming α 1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased K ATP current and CS cardiac pathophysiology.C antu syndrome (CS), characterized by hypertrichosis, osteochondrodysplasia, and multiple cardiovascular abnormalities (1), is caused by gain-of-function (GOF) mutations in the genes encoding the pore-forming (Kir6.1, KCNJ8) and regulatory (SUR2, ABCC9) subunits of the predominantly cardiovascular isoforms of the K ATP channel (2-5). Because the same disease features arise from mutations in either of these subunits, it is concluded that CS arises from increased K ATP channel activity, as opposed to any nonelectrophysiologic function of either subunit.However, this conclusion does not provide immediate explanation for many CS features. In the myocardium, for example, acute activation of K ATP channels results in shortening of the action potential (AP), with concomitant reduction of both calcium entry and contractility (6). The naïve prediction in CS would therefore be that K ATP GOF mutations should shorten the AP, reduce contractility, and reduce cardiac output. We previously reported high cardiac output with low systemic vascular resistance in CS (7). Cantu syndrome cardiac pathology is therefore opposite to prediction, and also unlike classical hypertrophic or dilated cardiomyopathies, in that the ventricle is dilated, but there is increased cardiac output. Here we characterize CS cardiac pathology in patients, and explore the mechanistic basis using mice that express K ATP GOF mutant subunits in the heart and vasculature. ResultsLow Blood Pressure in CS Patients. Eleven CS individuals (five male, six female, aged 17 mo to 47 y), all harboring ABCC9 mutations (Table S1), participated in CS research clinics at St. Louis Children's Hospital. Five had been previously followed at this institution (7) and the remainder were enrolled via the CS Interest Group (www.cantu-syndrome.org). Patient demographic data, genotype, and available cardiac historical, physical, and test information are summarized in Table S1. Most patients had no recalled cardiac symptomatology, although prior office notes revealed episodes of chest pain, f...

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Section: Feedback Control Via L-type Ca Current In Compensated Cardiacmentioning

confidence: 99%

mentioning

confidence: 99%

K _ATP channel gain-of-function leads to increased myocardial L-type Ca ²⁺ current and contractility in Cantu syndrome

Levin

Singh

Zhang

et al. 2016

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

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“…ABCC9 , which encodes the predominant sulfonylurea receptor (SUR2) isoform in the cardiovascular system, have been identified in 18 of 25 individuals with CS 11,12 . Two studies 13,14 have also identified KCNJ8 mutations in CS patients. The demonstration that CS can result from mutations in Kir6.1 14 or SUR2 confirms that CS results from GOF in K ATP channels formed from these subunits.…”

Section: Introductionmentioning

confidence: 99%

“…Two studies 13,14 have also identified KCNJ8 mutations in CS patients. The demonstration that CS can result from mutations in Kir6.1 14 or SUR2 confirms that CS results from GOF in K ATP channels formed from these subunits.…”

Section: Introductionmentioning

confidence: 99%

Electrophysiologic consequences of KATP gain of function in the heart: Conduction abnormalities in Cantu syndrome

et al. 2015

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Background Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities. Objective To better understand the electrophysiological consequences of such GOF mutations in the heart. Methods We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and carried out patch-clamp experiments on isolated ventricular myocytes, invasive electrophysiology on anesthetized mice. Results In Kir6.1-GOF ventricular myocytes, KATP channels show decreased ATP sensitivity, but there is no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice reveal AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiological analyses reveal slowing of conduction and conduction failure through the AV node, but no increase in susceptibility to atrial or ventricular ectopic activity. Surface electrocardiograms recorded from CS patients also demonstrate first degree AV block, and fascicular block. Conclusions The primary electrophysiological consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients, who carry KATP GOF mutations.

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“…Cantú syndrome has been associated with a variety of less classical phenotypes such as ovarian agenesis [5], cerebral artery dilation [6], bronchopulmonary dysplasia [7], pericardial effusion [8], and pituitary adenoma [9]. One prior patient with a KCNJ8 mutation was found to have growth hormone deficiency without evidence of thyroid or adrenal axis involvement [10]. A patient in Italy clinically diagnosed with Cantú syndrome was diagnosed with panhypopituitarism but this patient did not have confirmed Cantú syndrome by genetic testing [11].…”

Section: Discussionmentioning

confidence: 99%

Cantú Syndrome with panhypopituitarism

Liu¹,

Darshan²,

Romayne³

2018

Med Res Innov

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Cantú Syndrome Resulting from Activating Mutation in theKCNJ8Gene

Cited by 97 publications

References 29 publications

K _ATP channel gain-of-function leads to increased myocardial L-type Ca ²⁺ current and contractility in Cantu syndrome

K _ATP channel gain-of-function leads to increased myocardial L-type Ca ²⁺ current and contractility in Cantu syndrome

Electrophysiologic consequences of KATP gain of function in the heart: Conduction abnormalities in Cantu syndrome

Cantú Syndrome with panhypopituitarism

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Cantú Syndrome Resulting from Activating Mutation in theKCNJ8Gene

Cited by 97 publications

References 29 publications

K ATP channel gain-of-function leads to increased myocardial L-type Ca 2+ current and contractility in Cantu syndrome

K ATP channel gain-of-function leads to increased myocardial L-type Ca 2+ current and contractility in Cantu syndrome

Electrophysiologic consequences of KATP gain of function in the heart: Conduction abnormalities in Cantu syndrome

Cantú Syndrome with panhypopituitarism

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K _ATP channel gain-of-function leads to increased myocardial L-type Ca ²⁺ current and contractility in Cantu syndrome

K _ATP channel gain-of-function leads to increased myocardial L-type Ca ²⁺ current and contractility in Cantu syndrome