Gain-of-function Mutation S422L in the KCNJ8-encoded Cardiac K(ATP) Channel Kir6.1 As a Pathogenic Substrate for J-wave Syndromes

Overview

Journal Heart Rhythm

Publisher Elsevier

Specialty Cardiology & Vascular Diseases

Date 2010 Jun 19

PMID 20558321

Citations 119

Authors

Argelia Medeiros-Domingo

Bi-Hua Tan

Lia Crotti

David J Tester

Lee Eckhardt

Alessandra Cuoretti

Stacie L Kroboth

Chunhua Song

Qing Zhou

Doug Kopp

Peter J Schwartz

Jonathan C Makielski

Michael J Ackerman

Affiliations

Soon will be listed here.

Abstract

Background: J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L.

Objective: The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes.

Methods: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique.

Results: One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. K(ATP) current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 16-21; P <.05).

Conclusion: These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.

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References

Morrissey A, Rosner E, Lanning J, Parachuru L, Chowdhury P, Han S . Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature. BMC Physiol. 2005; 5(1):1. PMC: 546210. DOI: 10.1186/1472-6793-5-1. View

Chen Q, Kirsch G, Zhang D, Brugada R, Brugada J, Brugada P . Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998; 392(6673):293-6. DOI: 10.1038/32675. View

Bryan J, Munoz A, Zhang X, Dufer M, Drews G, Krippeit-Drews P . ABCC8 and ABCC9: ABC transporters that regulate K+ channels. Pflugers Arch. 2006; 453(5):703-18. DOI: 10.1007/s00424-006-0116-z. View

Zhang H, Flagg T, Nichols C . Cardiac sarcolemmal K(ATP) channels: Latest twists in a questing tale!. J Mol Cell Cardiol. 2009; 48(1):71-5. PMC: 2813340. DOI: 10.1016/j.yjmcc.2009.07.002. View

Hu D, Barajas-Martinez H, Burashnikov E, Springer M, Wu Y, Varro A . A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype. Circ Cardiovasc Genet. 2009; 2(3):270-8. PMC: 2801870. DOI: 10.1161/CIRCGENETICS.108.829192. View

Chutkow W, Makielski J, Nelson D, Burant C, Fan Z . Alternative splicing of sur2 Exon 17 regulates nucleotide sensitivity of the ATP-sensitive potassium channel. J Biol Chem. 1999; 274(19):13656-65. DOI: 10.1074/jbc.274.19.13656. View

Miki T, Suzuki M, Shibasaki T, Uemura H, Sato T, Yamaguchi K . Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med. 2002; 8(5):466-72. DOI: 10.1038/nm0502-466. View

Tong X, Porter L, Liu G, Dhar-Chowdhury P, Srivastava S, Pountney D . Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits. Am J Physiol Heart Circ Physiol. 2006; 291(2):H543-51. PMC: 2950019. DOI: 10.1152/ajpheart.00051.2006. View

Tester D, Will M, Ackerman M . Mutation detection in congenital long QT syndrome: cardiac channel gene screen using PCR, dHPLC, and direct DNA sequencing. Methods Mol Med. 2006; 128:181-207. DOI: 10.1385/1-59745-159-2:181. View

10.

Norstrand D, Valdivia C, Tester D, Ueda K, London B, Makielski J . Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome. Circulation. 2007; 116(20):2253-9. PMC: 3332545. DOI: 10.1161/CIRCULATIONAHA.107.704627. View

11.

Foell J, Balijepalli R, Delisle B, Yunker A, Robia S, Walker J . Molecular heterogeneity of calcium channel beta-subunits in canine and human heart: evidence for differential subcellular localization. Physiol Genomics. 2004; 17(2):183-200. DOI: 10.1152/physiolgenomics.00207.2003. View

12.

Amin A, Tan H, Wilde A . Cardiac ion channels in health and disease. Heart Rhythm. 2009; 7(1):117-26. DOI: 10.1016/j.hrthm.2009.08.005. View

13.

Kapplinger J, Tester D, Salisbury B, Carr J, Harris-Kerr C, Pollevick G . Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009; 6(9):1297-303. PMC: 3049907. DOI: 10.1016/j.hrthm.2009.05.021. View

14.

Kuniyasu A, Kaneko K, Kawahara K, Nakayama H . Molecular assembly and subcellular distribution of ATP-sensitive potassium channel proteins in rat hearts. FEBS Lett. 2003; 552(2-3):259-63. DOI: 10.1016/s0014-5793(03)00936-0. View

15.

Zingman L, Alekseev A, Hodgson-Zingman D, Terzic A . ATP-sensitive potassium channels: metabolic sensing and cardioprotection. J Appl Physiol (1985). 2007; 103(5):1888-93. DOI: 10.1152/japplphysiol.00747.2007. View

16.

Rosso R, Kogan E, Belhassen B, Rozovski U, Scheinman M, Zeltser D . J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol. 2008; 52(15):1231-8. DOI: 10.1016/j.jacc.2008.07.010. View

17.

Nichols C . KATP channels as molecular sensors of cellular metabolism. Nature. 2006; 440(7083):470-6. DOI: 10.1038/nature04711. View

18.

Cordeiro J, Marieb M, Pfeiffer R, Calloe K, Burashnikov E, Antzelevitch C . Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome. J Mol Cell Cardiol. 2009; 46(5):695-703. PMC: 2668128. DOI: 10.1016/j.yjmcc.2009.01.014. View

19.

Haissaguerre M, Chatel S, Sacher F, Weerasooriya R, Probst V, Loussouarn G . Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol. 2009; 20(1):93-8. DOI: 10.1111/j.1540-8167.2008.01326.x. View

20.

Babenko A, Aguilar-Bryan L, Bryan J . A view of sur/KIR6.X, KATP channels. Annu Rev Physiol. 1998; 60:667-87. DOI: 10.1146/annurev.physiol.60.1.667. View