Alternative titles; symbols
HGNC Approved Gene Symbol: KCNJ8
Cytogenetic location: 12p12.1 Genomic coordinates (GRCh38): 12:21,764,955-21,774,706 (from NCBI)
Inagaki et al. (1995) isolated a cDNA from a rat pancreatic islet cell library that encodes a member of the inward rectifier potassium channel family. The predicted 424-amino acid protein, which they designated uKATP-1, has 2 transmembrane domains and shares 43 to 46% identity with other inward rectifier potassium channels, including ROMK1 (600359), IRK1 (600681), GIRK1 (601534), and cKATP-1 (600734). When the protein was expressed in Xenopus oocytes, a weak rectifier activity was demonstrated that was blocked with Ba(+2) and activated by diazoxide. Northern blots showed that the mRNA is widely expressed in various tissues of the rat. Inagaki et al. (1995) cloned the human gene, designated KCNJ8. The predicted human protein is 98% identical to that of the rat.
Inagaki et al. (1995) showed that the KCNJ8 gene contains 3 exons spanning approximately 10 kb.
Inagaki et al. (1995) mapped the KCNJ8 gene to 12p11.23 by fluorescence in situ hybridization.
See 600935.0001 for discussion of a possible association between variation in the KCNJ8 gene and Brugada syndrome (see 601144) or ventricular fibrillation with early repolarization (see 613601).
For discussion of a possible association between Cantu syndrome (see 239850) and variation in the KCNJ8 gene, see 600935.0002 and 600935.0003.
Miki et al. (2002) found that mice lacking the Kir6.1 gene had a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block, as seen on the electrocardiogram. The potassium channel opener pinacidil did not induce potassium channels in vascular smooth muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil. Administration of methylergometrine, a vasoconstrictive agent, elicited ST elevation followed by cardiac death in Kir6.1-null mice but not in wildtype mice, indicating a phenotype characterized by hypercontractility of coronary arteries and resembling Prinzmetal (or variant) angina in humans (Prinzmetal et al., 1959). Prinzmetal angina occurs exclusively at rest and is associated with elevation of ST segments on EKG during the attack. Although the attack disappears spontaneously in most cases, it can lead to myocardial infarction, severe AV block, life-threatening ventricular tachycardia, and sudden death if the coronary vasospasm is prolonged (MacAlpin, 1993). The elevated ST segments on EKG during the attack are diagnostic, as is induction of coronary spasm by ergot alkaloids or acetylcholine. Vasospastic angina is more common in Japanese than in Caucasians (Beltrame et al., 1999; Pristipino et al., 2000). Miki et al. (2002) concluded that the Kir6.1-containing potassium channel is critical in the regulation of vascular tone, especially in the coronary arteries, and its disruption may cause Prinzmetal angina. They suggested that it will be important to learn whether genetic differences in the KIR6.1 gene are associated with Prinzmetal angina in various populations.
From a screen of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Croker et al. (2007) identified a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and a sensitization of approximately 20,000-fold to lipopolysaccharide, poly(I.C), and immunostimulatory (CpG) DNA. The LPS hypersensitivity phenotype was not suppressed by mutations in other genes contributing to LPS responses, and resulted from an abnormality extrinsic to hematopoietic cells. The phenotype was due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 (601439) to form an ATP-sensitive potassium channel expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, Croker et al. (2007) found that suppression of dSUR by RNA interference similarly caused hypersensitivity to infection by flock house virus. Thus, K(ATP) evolved to serve a homeostatic function during infection, an in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on Toll-like receptor (TLR; see 601194) and/or MDA5 (606951) immunoreceptors.
This variant is classified as a variant of unknown significance because its contribution to Brugada syndrome (see 601144) or to ventricular fibrillation with early repolarization (see 613601) has not been confirmed. See Veeramah et al. (2014) and Cooper et al. (2014).
In a 14-year-old girl with recurrent episodes of ventricular fibrillation (VF) and prominent early repolarization, Haissaguerre et al. (2009) analyzed 21 cardiac ion channel-associated genes and identified heterozygosity for a c.1265C-T transition in exon 3 of the KCNJ8 gene, resulting in a ser422-to-leu (S422L) substitution at a highly conserved residue. Flecainide challenge in the proband did not unmask a Brugada pattern on electrocardiography (ECG). The mutation was not found in her unaffected mother or in 764 control alleles; her father did not consent to clinical or genetic testing. The KCNJ8 S422L variant was not detected in 156 additional VF patients with early repolarization.
Medeiros-Domingo et al. (2010) sequenced the KCNJ8 gene in 87 patients with Brugada syndrome and 14 with early repolarization syndrome and identified heterozygosity for the S422L mutation in 2 patients: one was a 30-year-old man diagnosed with Brugada syndrome; the other was a 21-year-old man with a history of syncope and ventricular tachycardia who had an early repolarization pattern on ECG, in whom no drug challenge to unmask a Brugada pattern was reported. The mutation was not found in 1,200 control alleles (p = 0.02). Voltage-clamp studies in COS-1 cells showed a 60 to 67% increase in K(ATP) current density with the S422L mutant compared to wildtype, indicating a marked gain of function.
Barajas-Martinez et al. (2012) sequenced the KCNJ8 gene in 204 patients with what they designated 'J-wave syndromes,' encompassing Brugada syndrome and 'early repolarization syndrome.' They identified the S422L mutation in 3 unrelated male patients with Brugada syndrome and confirmed the mutation in the female patient with VF and early repolarization who was originally studied by Haissaguerre et al. (2009). The S422L mutation, which was not found in 430 control alleles, was also detected in the affected mother of 1 of the male probands; both patients exhibited atrial fibrillation and first-degree atrioventricular block. The 5 patients with the S422L mutation were also screened for variants in 22 known Brugada syndrome- or early repolarization-associated genes; heterozygosity for a D601E polymorphism in the CACNB2 gene (600003) was detected in the mother and son with Brugada syndrome and in the female patient with VF and early repolarization. Whole-cell patch-clamp studies demonstrated a 2-fold gain of function with the S422L KCNJ8 mutation compared to wildtype; in addition, at physiologic levels of intracellular ATP, wildtype channels were totally inhibited, whereas mutant channels remained partially open. Barajas-Martinez et al. (2012) concluded that KCNJ8 is a susceptibility gene for both Brugada and early repolarization syndromes, and suggested that S422L might be a hotspot mutation.
Crotti et al. (2012) analyzed 12 Brugada syndrome susceptibility genes in 129 unrelated patients with possible or probable Brugada syndrome. In an asymptomatic 30-year-old man with a type 1 Brugada syndrome ECG pattern, they identified heterozygosity for the S422L mutation in the KCNJ8 gene.
In an Ashkenazi Jewish family quartet in which the female proband died from early infantile epileptic encephalopathy (EIEE13; 614558) due to a mutation in the SCN8A gene (600702.0002), Veeramah et al. (2014) reexamined the results from whole-genome sequencing performed by Veeramah et al. (2012). The authors found that the unaffected parents as well as the deceased proband were heterozygous for the S422L mutation in the KCNJ8 gene, whereas the proband's healthy 12-year-old brother was homozygous for S422L. Serial ECGs in the S422L homozygote showed no clinically significant abnormalities, whereas his heterozygous father showed subtle J-point elevation. Veeramah et al. (2014) genotyped the S422L variant in a panel of 722 individuals from 22 European, Middle Eastern non-Jewish, Ashkenazi Jewish, and non-Ashkenazi Jewish populations and found that the S422L allele was present at a significantly higher frequency in Ashkenazi Jews (approximately 4%) than in other populations, which had frequencies less than 0.25%. Veeramah et al. (2014) suggested that either previous studies implicating S422L as pathogenic for J-wave syndromes failed to account for European population structure and that the variant was likely benign, or that Ashkenazi Jews might be at significantly increased risk of J-wave syndromes and ultimately sudden cardiac death.
Cooper et al. (2014) performed functional analysis of the S422L mutant in recombinant COS cells and observed similar activity to that seen with wildtype KCNJ8.
This variant is classified as a variant of unknown significance because its contribution to Cantu syndrome (see 239850) has not been confirmed.
By whole-genome analysis in a 6-year-old boy with Cantu syndrome who was negative for mutation in the ABCC9 gene (601439), Brownstein et al. (2013) identified heterozygosity for a de novo c.193G-A transition in exon 1 of the KCNJ8 gene, resulting in a val65-to-met (V65M) substitution at a highly conserved residue within the amino terminus. No functional analysis of the V65M mutant was reported. Although the patient had no abnormalities on ECG, he did exhibit vascular features previously unreported in Cantu syndrome, including a dilated aortic root, dilated hepatic and celiac arteries, dilated and tortuous intrahepatic arteries and veins, tortuous cerebral arteries, and multiple venous defects in the brain. Brownstein et al. (2013) also detected compound heterozygous missense variants in the EOMES gene (604615) in the proband; both variants were also found in the NHLBI Exome Variant Server database, and the authors did not believe them to be causative of the patient's multiorgan disorder.
This variant is classified as a variant of unknown significance because its contribution to Cantu syndrome (see 239850) has not been confirmed.
In a 13-year-old boy with Cantu syndrome who was originally described by Engels et al. (2002) and who was found to be negative for mutation in the ABCC9 gene (601439) by van Bon et al. (2012), Cooper et al. (2014) identified heterozygosity for a de novo c.526T-A transversion in the KCNJ8 gene, resulting in a cys176-to-ser (C176S) substitution at a highly conserved residue. The mutation was not present in the proband's unaffected parents, in 2,096 in-house exomes, or in 6,503 exomes in the NHLBI Exome Variant Server database. Functional analysis in recombinant COS cells showed marked gain of function with the C176S mutant compared to wildtype, even under basal metabolic conditions. Patch-clamp experiments demonstrated that the enhanced activity of C176S mutant channels results from reduced ATP sensitivity, and indicated that the heterozygous C176S mutation will overactivate any native K(ATP) channel in which it is present.
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Beltrame, J. F., Sasayama, S., Maseri, A. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients. J. Am. Coll. Cardiol. 33: 1442-1452, 1999. [PubMed: 10334407] [Full Text: https://doi.org/10.1016/s0735-1097(99)00073-x]
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Cooper, P. E., Reutter, H., Woelfle, J., Engels, H., Grange, D. K., van Haaften, G., van Bon, B. W., Hoischen, A., Nichols, C. G. Cantu syndrome resulting from activating mutation in the KCNJ8 gene. Hum. Mutat. 35: 809-813, 2014. [PubMed: 24700710] [Full Text: https://doi.org/10.1002/humu.22555]
Croker, B., Crozat, K., Berger, M., Xia, Y., Sovath, S., Schaffer, L., Eleftherianos, I., Imler, J.-L., Beutler, B. ATP-sensitive potassium channels mediate survival during infection in mammals and insects. Nature Genet. 39: 1453-1460, 2007. [PubMed: 18026101] [Full Text: https://doi.org/10.1038/ng.2007.25]
Crotti, L., Marcou, C. A., Tester, D. J., Castelletti, S., Giudicessi, J. R., Torchio, M., Medeiros-Domingo, A., Simone, S., Will, M. L., Dagradi, F., Schwartz, P. J., Ackerman, M. J. Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. J. Am. Coll. Cardiol. 60: 1410-1418, 2012. [PubMed: 22840528] [Full Text: https://doi.org/10.1016/j.jacc.2012.04.037]
Engels, H., Bosse, K., Ehrbrecht, A., Zahn, S., Hoischen, A., Propping, P., Bindl, L., Reutter, H. Further case of Cantu syndrome: exclusion of cryptic subtelomeric chromosome aberrations. Am. J. Med. Genet. 111: 205-209, 2002. [PubMed: 12210352] [Full Text: https://doi.org/10.1002/ajmg.10560]
Haissaguerre, M., Chatel, S., Sacher, F., Weerasooriya, R., Probst, V., Loussouarn, G., Horlitz, M., Liersch, R., Schulze-Bahr, E., Wilde, A., Kaab, S., Koster, J., Rudy, Y., Le Marec, H., Schott, J. J. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/K(ATP) channel. J. Cardiovasc. Electrophysiol. 20: 93-98, 2009. [PubMed: 19120683] [Full Text: https://doi.org/10.1111/j.1540-8167.2008.01326.x]
Inagaki, N., Inazawa, J., Seino, S. cDNA sequence, gene structure, and chromosomal localization of the human ATP-sensitive potassium channel, uK(ATP)-1, gene (KCNJ8). Genomics 30: 102-104, 1995. [PubMed: 8595887] [Full Text: https://doi.org/10.1006/geno.1995.0018]
Inagaki, N., Tsuura, Y., Namba, N., Masuda, K., Gonoi, T., Horie, M., Seino, Y., Mizuta, M., Seino, S. Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J. Biol. Chem. 270: 5691-5694, 1995. [PubMed: 7890693] [Full Text: https://doi.org/10.1074/jbc.270.11.5691]
MacAlpin, R. N. Cardiac arrest and sudden unexpected death in variant angina: complications of coronary spasm that can occur in the absence of severe organic coronary stenosis. Am. Heart J. 125: 1011-1017, 1993. [PubMed: 8465723] [Full Text: https://doi.org/10.1016/0002-8703(93)90108-l]
Medeiros-Domingo, A., Tan, B.-H., Crotti, L., Tester, D. J., Eckhardt, L., Cuoretti, A., Kroboth, S. L., Song, C., Zhou, Q., Kopp, D., Schwartz, P. J., Makielski, J. C., Ackerman, M. J. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm 7: 1466-1471, 2010. [PubMed: 20558321] [Full Text: https://doi.org/10.1016/j.hrthm.2010.06.016]
Miki, T., Suzuki, M., Shibasaki, T., Uemura, H., Sato, T., Yamaguchi, K., Koseki, H., Iwanaga, T., Nakaya, H., Seino, S. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nature Med. 8: 466-472, 2002. [PubMed: 11984590] [Full Text: https://doi.org/10.1038/nm0502-466]
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Pristipino, C., Beltrame, J. F., Finocchiaro, M. L., Hattori, R., Fujita, M., Mongiardo, R., Cianflone, D., Sanna, T., Sasayama, S., Maseri, A. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation 101: 1102-1108, 2000. [PubMed: 10715255] [Full Text: https://doi.org/10.1161/01.cir.101.10.1102]
van Bon, B. W. M., Gilissen, C., Grange, D. K., Hennekam, R. C. M., Kayserili, H., Engels, H., Reutter, H., Ostergaard, J. R., Morava, E., Tsiakas, K., Isidor, B., Le Merrer, M., and 9 others. Cantu syndrome is caused by mutations in ABCC9. Am. J. Hum. Genet. 90: 1094-1101, 2012. [PubMed: 22608503] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.014]
Veeramah, K. R., Karafet, T. M., Wolf, D., Samson, R. A., Hammer, M. F. The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews. Europ. J. Hum. Genet. 22: 94-98, 2014. [PubMed: 23632791] [Full Text: https://doi.org/10.1038/ejhg.2013.78]
Veeramah, K. R., O'Brien, J. E., Meisler, M. H., Cheng, X., Dib-Hajj, S. D., Waxman, S. G., Talwar, D., Girirajan, S., Eichler, E. E., Restifo, L. L., Erickson, R. P., Hammer, M. F. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am. J. Hum. Genet. 90: 502-512, 2012. [PubMed: 22365152] [Full Text: https://doi.org/10.1016/j.ajhg.2012.01.006]