A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Electrocardiography* ; Genetic Predisposition to Disease* ; Penetrance*; Asian People/*genetics ; Calcium Channels, L-Type/*genetics ; Mutation/*genetics; Action Potentials/drug effects ; Adult ; China ; Family ; Female ; Genetic Association Studies ; HEK293 Cells ; Heart Ventricles/drug effects ; Heart Ventricles/physiopathology ; Humans ; Isoproterenol/pharmacology ; Kinetics ; Male ; Models, Cardiovascular ; Mutant Proteins/metabolism ; NAV1.5 Voltage-Gated Sodium Channel/genetics ; Pedigree ; Syndrome ; Testosterone/pharmacology

Background: Early repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory.
Methods and Results: We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A (p.R1193Q) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation.
Conclusions: Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the SCN5A-R1193Q variant and sex. These findings suggest that phenotypes of ERS are modified by multiple genetic factors, which supports the theory that ERS may be an oligogenic disease.

J Am Coll Cardiol. 2015 Jul 28;66(4):470-7. (PMID: 26205599)
Circ Cardiovasc Genet. 2011 Apr;4(2):134-8. (PMID: 21282333)
Circ Res. 2013 Aug 16;113(5):617-31. (PMID: 23948586)
Cell Calcium. 2007 Jul;42(1):11-5. (PMID: 17173968)
Cardiol Rev. 2011 Sep-Oct;19(5):217-25. (PMID: 21808164)
Circulation. 2016 Apr 12;133(15):1520-9. (PMID: 27067089)
Int J Cardiol. 2014 Feb 15;171(3):431-42. (PMID: 24439875)
Circ Res. 2015 Jun 5;116(12):1919-36. (PMID: 26044248)
Heart Rhythm. 2010 Dec;7(12):1872-82. (PMID: 20817017)
Circ J. 2013;77(7):1799-806. (PMID: 23575362)
Nat Rev Cardiol. 2012 Jan 31;9(6):319-32. (PMID: 22290238)
Int J Mol Med. 2016 Mar;37(3):727-33. (PMID: 26820605)
Heart Rhythm. 2011 Jun;8(6):923-9. (PMID: 21295159)
J Am Heart Assoc. 2015 Jan 23;4(1):e001526. (PMID: 25616976)
Heart Rhythm. 2013 Dec;10(12):1932-63. (PMID: 24011539)
Heart Rhythm. 2016 Jul;13(7):1544-51. (PMID: 27005929)
Int J Mol Med. 2013 Sep;32(3):661-7. (PMID: 23799537)
J Mol Cell Cardiol. 2014 Mar;68:20-8. (PMID: 24378566)
Heart Rhythm. 2010 Oct;7(10):1466-71. (PMID: 20558321)
J Am Coll Cardiol. 2011 Aug 9;58(7):722-8. (PMID: 21816308)
Nature. 2016 Aug 17;536(7616):285-91. (PMID: 27535533)
Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1088-100. (PMID: 16565318)
ACS Chem Biol. 2011 Nov 18;6(11):1193-7. (PMID: 21932825)
Am J Cardiol. 2013 Aug 1;112(3):444-8. (PMID: 23642382)
Nat Clin Pract Cardiovasc Med. 2005 Aug;2(8):408-14. (PMID: 16119703)
Circ Cardiovasc Genet. 2009 Dec;2(6):552-7. (PMID: 20031634)
Eur Heart J. 2015 Nov 1;36(41):2793-867. (PMID: 26320108)
J Cardiovasc Electrophysiol. 2009 Jan;20(1):93-8. (PMID: 19120683)
N Engl J Med. 2008 May 8;358(19):2016-23. (PMID: 18463377)
Physiol Res. 2011;60(1):27-37. (PMID: 20945956)
J Med Genet. 2004 May;41(5):e66. (PMID: 15121794)
Neuron. 1997 Jul;19(1):185-96. (PMID: 9247274)
Circ Arrhythm Electrophysiol. 2011 Dec;4(6):874-81. (PMID: 22028457)
Heart Rhythm. 2012 Jan;9(1):77-83. (PMID: 21855521)
J Am Coll Cardiol. 2013 Sep 10;62(11):1015-9. (PMID: 23747791)

0 (CACNA1C protein, human)
0 (Calcium Channels, L-Type)
0 (Mutant Proteins)
0 (NAV1.5 Voltage-Gated Sodium Channel)
0 (SCN5A protein, human)
3XMK78S47O (Testosterone)
L628TT009W (Isoproterenol)

Date Created: 20170512 Date Completed: 20170911 Latest Revision: 20221207

20250114

PMC5426766

10.1371/journal.pone.0177532

28493952