Mutations in the potassium channel subunit KCNE1 are associated with early-onset familial atrial fibrillation

BMC Medical Genetics

Nicole Schmitt²  Jesper H Svendsen³  Stig Haunsø³  Henrik K Jensen⁴  Javad Jabbari¹  Jens-Peter David²  Annette B Steffensen²  Jonas B Nielsen¹  Bo H Bentzen²  Morten S Olesen¹ 

[1] Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;The Ion Channel Group, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 12.5.14, Copenhagen, N 2200, Denmark;Department of Surgery and Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;Department of Cardiology, Aarhus University Hospital, Skejby, Denmark

关键词: I_Ks current;    KCNE1;    K_V7.1;    Genetics;    Lone AF;   

Others  :  1177887
DOI  :  10.1186/1471-2350-13-24

 received in 2011-10-03, accepted in 2012-04-03,  发布年份 2012

【 摘 要 】

Background

Atrial fibrillation (AF) is the most common arrhythmia. The potassium current I_Ks is essential for cardiac repolarization. Gain-of-function mutations in K_V7.1, the pore-forming α-subunit of the I_Ks channel, have been associated with AF. We hypothesized that early-onset lone AF is associated with mutations in the I_Ks channel regulatory subunit KCNE1.

Methods

In 209 unrelated early-onset lone AF patients (< 40 years) the entire coding sequence of KCNE1 was bidirectionally sequenced. We analyzed the identified KCNE1 mutants electrophysiologically in heterologous expression systems.

Results

Two non-synonymous mutations G25V and G60D were found in KCNE1 that were not present in the control group (n = 432 alleles) and that have not previously been reported in any publicly available databases or in the exom variant server holding exom data from more than 10.000 alleles. Proband 1 (female, age 45, G25V) had onset of paroxysmal AF at the age of 39 years. Proband 2 (G60D) was diagnosed with lone AF at the age of 33 years. The patient has inherited the mutation from his mother, who also has AF. Both probands had no mutations in genes previously associated with AF. In heterologous expression systems, both mutants showed significant gain-of-function for I_Ks both with respect to steady-state current levels, kinetic parameters, and heart rate-dependent modulation.

Conclusions

Mutations in K_V7.1 leading to gain-of-function of I_Ks current have previously been described in lone AF, yet this is the first time a mutation in the beta-subunit KCNE1 is associated with the disease. This finding further supports the hypothesis that increased potassium current enhances AF susceptibility.

【 授权许可】

   
2012 Olesen et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Benjamin EJ, Wolf PA, D'Agostino RB, et al.: Impact of atrial fibrillation on the risk of death: the Framingham heart study. Circulation 1998, 98(10):946-952.
• [2]Fuster V, Rydén LE, Cannom DS, et al.: ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-excutive summary. Rev Port Cardiol 2007, 26(4):383-446.
• [3]Stewart S, Hart CL, Hole DJ, McMurray JJ: Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study. Heart 2001, 86(5):516-521.
• [4]Go AS, Hylek EM, Phillips KA, et al.: Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA 2001, 285(18):2370-2375.
• [5]Psaty BM, Manolio TA, Kuller LH, et al.: Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997, 96(7):2455-2461.
• [6]Mahida S, Lubitz SA, Rienstra M, Milan DJ, Ellinor PT: Monogenic Atrial Fibrillation as Pathophysiological Paradigms. Cardiovasc Res 2010. Available at: http://cardiovascres.oxfordjournals.org/content/early/2010/11/30/cvr.cvq381.abstract webcite. Åbnet December 21, 2010.
• [7]Gudbjartsson DF, Arnar DO, Helgadottir A, et al.: Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007, 448(7151):353-357.
• [8]Olesen MS, Holst AG, Jabbari J, et al.: Genetic Loci on Chromosomes 4q25, 7p31, and 12p12 Are Associated With Onset of Lone Atrial Fibrillation Before the Age of 40 Years. [http://www.ncbi.nlm.nih.gov/pubmed/22336519] webciteThe Canadian Journal of Cardiology 2012.
• [9]Olesen MS, Jespersen T, Nielsen JB, et al.: Mutations in sodium channel β-subunit SCN3B are associated with early-onset lone atrial fibrillation. Cardiovasc Res 2011, 89(4):786-793.
• [10]Nattel S: New ideas about atrial fibrillation 50 years on. Nature 2002, 415(6868):219-226.
• [11]Moe GK: Evidence for reentry as a mechanism of cardiac arrhythmias. Rev Physiol Biochem Pharmacol 1975, 72:55-81.
• [12]Yang Y, Li J, Lin X, et al.: Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation. J Hum Genet 2009, 54(5):277-283.
• [13]Lundby A, Tseng G-N, Schmitt N: Structural basis for K(V)7.1-KCNE(x) interactions in the I(Ks) channel complex. Heart Rhythm 2010, 7(5):708-713.
• [14]Olesen MS, Jabbari J, Holst AG, et al.: Screening of KCNN3 in patients with early-onset lone atrial fibrillation. Europace 2011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21398315 webcite Åbnet April 18, 2011
• [15]Nielsen JB, Olesen MS, Tangø M, et al.: Incomplete right bundle branch block: a novel electrocardiographic marker for lone atrial fibrillation. Europace 2011, 13(2):182-187.
• [16]Johnson JN, Ackerman MJ: QTc: how long is too long? Br J Sports Med 2009, 43(9):657-662.
• [17]Barhanin J, Lesage F, Guillemare E, et al.: K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1996, 384(6604):78-80.
• [18]Lundby A, Ravn LS, Svendsen JH, Olesen S-P, Schmitt N: KCNQ1 mutation Q147R is associated with atrial fibrillation and prolonged QT interval. Heart Rhythm 2007, 4(12):1532-1541.
• [19]Sanguinetti MC, Curran ME, Zou A, et al.: Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996, 384(6604):80-83.
• [20]Anon: Exome Variant Server, NHLBI Exome Sequencing Project (ESP), Seattle, WA[http://evs.gs.washington.edu/EVS/] webcite [10 juli, 2011 accessed]
• [21]Serre D, Gurd S, Ge B, et al.: Differential allelic expression in the human genome: a robust approach to identify genetic and epigenetic Cis-acting mechanisms regulating gene expression. PLoS Genet 2008, 4(2):e1000006.
• [22]Zhang Y, Rohde C, Tierling S, et al.: DNA methylation analysis of chromosome 21 gene promoters at single base pair and single allele resolution. PLoS Genet 2009, 5(3):e1000438.
• [23]Abraham RL, Yang T, Blair M, Roden DM, Darbar D: Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation. J Mol Cell Cardiol 2010, 48(1):181-190.
• [24]Zeng Z, Tan C, Teng S, et al.: The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population. Cardiology 2007, 108(2):97-103.
• [25]Lai L-P, Su M-J, Yeh H-M, et al.: Association of the human minK gene 38 G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J 2002, 144(3):485-490.
• [26]Ehrlich JR, Zicha S, Coutu P, Hébert TE, Nattel S: Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization. Cardiovasc Res 2005, 67(3):520-528.
• [27]Wang YH, Jiang M, Xu XL, et al.: Gating-related molecular motions in the extracellular domain of the IKs channel: implications for IKs channelopathy. J Membr Biol 2011, 239(3):137-156.
• [28]Melman YF, Domènech A, de la Luna S, McDonald TV: Structural determinants of KvLQT1 control by the KCNE family of proteins. J Biol Chem 2001, 276(9):6439-6444.
• [29]Kang C, Tian C, Sönnichsen FD, et al.: Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel. Biochemistry 2008, 47(31):7999-8006.
• [30]Melman YF, Krumerman A, McDonald TV: A single transmembrane site in the KCNE-encoded proteins controls the specificity of KvLQT1 channel gating. J Biol Chem 2002, 277(28):25187-25194.
• [31]Newton-Cheh C, Eijgelsheim M, Rice KM, et al.: Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet 2009, 41(4):399-406.
• [32]Pai GR, Rawles JM: The QT interval in atrial fibrillation. Br Heart J 1989, 61(6):510-513.
• [33]Chen Y-H, Xu S-J, Bendahhou S, et al.: KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003, 299(5604):251-254.
• [34]Johnson JN, Tester DJ, Perry J, et al.: Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. Heart Rhythm 2008, 5(5):704-709.
• [35]Giudicessi JR, Ye D, Tester DJ, et al.: Transient Outward Current (Ito) Gain-of-Function Mutations in the KCND3-Encoded Kv4.3 Potassium Channel and Brugada Syndrome. Heart Rhythm, in press. Available at: http://www.sciencedirect.com/science/article/B7GW9-527GJC8-2/2/89c6a7e6ed6b2ab449934bf44708dfc8 webcite Åbnet April 2, 2011.
• [36]Terrenoire C, Clancy CE, Cormier JW, Sampson KJ, Kass RS: Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation. Circ Res 2005, 96(5):e25-e34.
• [37]Shimizu K, Shintani Y, Ding W-G, Matsuura H, Bamba T: Potentiation of slow component of delayed rectifier K(+) current by cGMP via two distinct mechanisms: inhibition of phosphodiesterase 3 and activation of protein kinase G. Br J Pharmacol 2002, 137(1):127-137.