9u7f

Structural highlights

Disease

KCNQ1_HUMAN Defects in KCNQ1 are the cause of long QT syndrome type 1 (LQT1) [MIM:192500; also known as Romano-Ward syndrome (RWS). Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT1 inheritance is an autosomal dominant.^{[1] [2] [3] [4] [5] [6] [7]} [:]^{[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]} Defects in KCNQ1 are the cause of Jervell and Lange-Nielsen syndrome type 1 (JLNS1) [MIM:220400. JLNS1 is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death.^{[28] [29] [30]} Defects in KCNQ1 are the cause of familial atrial fibrillation type 3 (ATFB3) [MIM:607554. Atrial fibrillation is a common disorder of cardiac rhythm that is hereditary in a small subgroup of patients. It is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.^[31] Defects in KCNQ1 are the cause of short QT syndrome type 2 (SQT2) [MIM:609621. Short QT syndromes are heart disorders characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. They cause syncope and sudden death.^[32]

Function

KCNQ1_HUMAN Probably important in cardiac repolarization. Associates with KCNE1 (MinK) to form the I(Ks) cardiac potassium current. Elicits a rapidly activating, potassium-selective outward current. Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current in CHO cells in which cloned KCNQ1/KCNE1 channels were coexpressed with M1 muscarinic receptors. May associate also with KCNE3 (MiRP2) to form the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions, which is reduced in cystic fibrosis and pathologically stimulated in cholera and other forms of secretory diarrhea.

References

1. ↑ Wiener R, Haitin Y, Shamgar L, Fernandez-Alonso MC, Martos A, Chomsky-Hecht O, Rivas G, Attali B, Hirsch JA. The KCNQ1 (Kv7.1) C-terminus, a multi-tieredscaffold for subunit assembly and protein interaction. J Biol Chem. 2007 Dec 29;. PMID:18165683 doi:M707541200
2. ↑ Itoh T, Tanaka T, Nagai R, Kikuchi K, Ogawa S, Okada S, Yamagata S, Yano K, Yazaki Y, Nakamura Y. Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome. Hum Genet. 1998 Sep;103(3):290-4. PMID:9799083
3. ↑ Neyroud N, Richard P, Vignier N, Donger C, Denjoy I, Demay L, Shkolnikova M, Pesce R, Chevalier P, Hainque B, Coumel P, Schwartz K, Guicheney P. Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome. Circ Res. 1999 Feb 19;84(3):290-7. PMID:10024302
4. ↑ Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996 Jan;12(1):17-23. PMID:8528244 doi:http://dx.doi.org/10.1038/ng0196-17
5. ↑ Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, Jenkins-West T, Blanar MA. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation. 1997 Sep 16;96(6):1733-6. PMID:9323054
6. ↑ Russell MW, Dick M 2nd, Collins FS, Brody LC. KVLQT1 mutations in three families with familial or sporadic long QT syndrome. Hum Mol Genet. 1996 Sep;5(9):1319-24. PMID:8872472
7. ↑ de Jager T, Corbett CH, Badenhorst JC, Brink PA, Corfield VA. Evidence of a long QT founder gene with varying phenotypic expression in South African families. J Med Genet. 1996 Jul;33(7):567-73. PMID:8818942
8. ↑ Tanaka T, Nagai R, Tomoike H, Takata S, Yano K, Yabuta K, Haneda N, Nakano O, Shibata A, Sawayama T, Kasai H, Yazaki Y, Nakamura Y. Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. Circulation. 1997 Feb 4;95(3):565-7. PMID:9024139
9. ↑ Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret G, Schwartz K, Coumel P, Guicheney P. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation. 1997 Nov 4;96(9):2778-81. PMID:9386136
10. ↑ van den Berg MH, Wilde AA, Robles de Medina EO, Meyer H, Geelen JL, Jongbloed RJ, Wellens HJ, Geraedts JP. The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene. Hum Genet. 1997 Sep;100(3-4):356-61. PMID:9272155
11. ↑ Wollnik B, Schroeder BC, Kubisch C, Esperer HD, Wieacker P, Jentsch TJ. Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias. Hum Mol Genet. 1997 Oct;6(11):1943-9. PMID:9302275
12. ↑ Li H, Chen Q, Moss AJ, Robinson J, Goytia V, Perry JC, Vincent GM, Priori SG, Lehmann MH, Denfield SW, Duff D, Kaine S, Shimizu W, Schwartz PJ, Wang Q, Towbin JA. New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation. 1998 Apr 7;97(13):1264-9. PMID:9570196
13. ↑ Priori SG, Schwartz PJ, Napolitano C, Bianchi L, Dennis A, De Fusco M, Brown AM, Casari G. A recessive variant of the Romano-Ward long-QT syndrome? Circulation. 1998 Jun 23;97(24):2420-5. PMID:9641694
14. ↑ Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT. Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. Genomics. 1998 Jul 1;51(1):86-97. PMID:9693036 doi:S0888-7543(98)95361-7
15. ↑ Saarinen K, Swan H, Kainulainen K, Toivonen L, Viitasalo M, Kontula K. Molecular genetics of the long QT syndrome: two novel mutations of the KVLQT1 gene and phenotypic expression of the mutant gene in a large kindred. Hum Mutat. 1998;11(2):158-65. PMID:9482580 doi:<158::AID-HUMU9>3.0.CO;2-F 10.1002/(SICI)1098-1004(1998)11:2<158::AID-HUMU9>3.0.CO;2-F
16. ↑ Ackerman MJ, Schroeder JJ, Berry R, Schaid DJ, Porter CJ, Michels VV, Thibodeau SN. A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family. Pediatr Res. 1998 Aug;44(2):148-53. PMID:9702906
17. ↑ Denjoy I, Lupoglazoff JM, Donger C, Berthet M, Richard P, Neyroud N, Villain E, Lucet V, Coumel P, Guicheney P. [Congenital long QT syndrome. The value of genetics in prognostic evaluation] Arch Mal Coeur Vaiss. 1999 May;92(5):557-63. PMID:10367071
18. ↑ Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999 Feb 2;99(4):529-33. PMID:9927399
19. ↑ Larsen LA, Fosdal I, Andersen PS, Kanters JK, Vuust J, Wettrell G, Christiansen M. Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene. Eur J Hum Genet. 1999 Sep;7(6):724-8. PMID:10482963 doi:10.1038/sj.ejhg.5200323
20. ↑ Jongbloed RJ, Wilde AA, Geelen JL, Doevendans P, Schaap C, Van Langen I, van Tintelen JP, Cobben JM, Beaufort-Krol GC, Geraedts JP, Smeets HJ. Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. Hum Mutat. 1999;13(4):301-10. PMID:10220144 doi:<301::AID-HUMU7>3.0.CO;2-V 10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V
21. ↑ Larsen LA, Christiansen M, Vuust J, Andersen PS. High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants. Hum Mutat. 1999;13(4):318-27. PMID:10220146 doi:<318::AID-HUMU9>3.0.CO;2-F 10.1002/(SICI)1098-1004(1999)13:4<318::AID-HUMU9>3.0.CO;2-F
22. ↑ Franqueza L, Lin M, Shen J, Splawski I, Keating MT, Sanguinetti MC. Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits. J Biol Chem. 1999 Jul 23;274(30):21063-70. PMID:10409658
23. ↑ Chouabe C, Neyroud N, Richard P, Denjoy I, Hainque B, Romey G, Drici MD, Guicheney P, Barhanin J. Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. Cardiovasc Res. 2000 Mar;45(4):971-80. PMID:10728423
24. ↑ Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID:10973849
25. ↑ Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PMID:15840476 doi:10.1016/j.hrthm.2005.01.020
26. ↑ Thomas D, Khalil M, Alter M, Schweizer PA, Karle CA, Wimmer AB, Licka M, Katus HA, Koenen M, Ulmer HE, Zehelein J. Biophysical characterization of KCNQ1 P320 mutations linked to long QT syndrome 1. J Mol Cell Cardiol. 2010 Jan;48(1):230-7. doi: 10.1016/j.yjmcc.2009.06.009. Epub , 2009 Jun 21. PMID:19540844 doi:10.1016/j.yjmcc.2009.06.009
27. ↑ Aidery P, Kisselbach J, Schweizer PA, Becker R, Katus HA, Thomas D. Biophysical properties of mutant KCNQ1 S277L channels linked to hereditary long QT syndrome with phenotypic variability. Biochim Biophys Acta. 2011 Apr;1812(4):488-94. doi: 10.1016/j.bbadis.2011.01.008., Epub 2011 Jan 15. PMID:21241800 doi:10.1016/j.bbadis.2011.01.008
28. ↑ Chouabe C, Neyroud N, Richard P, Denjoy I, Hainque B, Romey G, Drici MD, Guicheney P, Barhanin J. Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. Cardiovasc Res. 2000 Mar;45(4):971-80. PMID:10728423
29. ↑ Neyroud N, Denjoy I, Donger C, Gary F, Villain E, Leenhardt A, Benali K, Schwartz K, Coumel P, Guicheney P. Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome. Eur J Hum Genet. 1998 Mar-Apr;6(2):129-33. PMID:9781056 doi:10.1038/sj.ejhg.5200165
30. ↑ Mohammad-Panah R, Demolombe S, Neyroud N, Guicheney P, Kyndt F, van den Hoff M, Baro I, Escande D. Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias. Am J Hum Genet. 1999 Apr;64(4):1015-23. PMID:10090886
31. ↑ Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003 Jan 10;299(5604):251-4. PMID:12522251 doi:10.1126/science.1077771
32. ↑ Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AA. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004 May 25;109(20):2394-7. PMID:15159330 doi:10.1161/01.CIR.0000130409.72142.FE
33. ↑ Zhong L, Lin X, Cheng X, Wan S, Hua Y, Nan W, Hu B, Peng X, Zhou Z, Zhang Q, Yang H, Noé F, Yan Z, Jiang D, Zhang H, Liu F, Xiao C, Zhou Z, Mou Y, Yu H, Ma L, Huang C, Wong VKW, Chung SK, Shen B, Jiang ZH, Neher E, Zhu W, Zhang J, Hou P. Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating. Cell Res. 2025 Nov;35(11):887-899. PMID:41034624 doi:10.1038/s41422-025-01182-9