Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young

Brittan S. Sutphin, Nicole J. Boczek, Héctor Barajas-Martínez, Dan Hu, Dan Ye, David J. Tester, Charles Antzelevitch, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Introduction: Perturbations in the CACNA1C-encoded L-type calcium channel α-subunit have been linked recently to heritable arrhythmia syndromes, including Timothy syndrome, Brugada syndrome, early repolarization syndrome, and long QT syndrome. These heritable arrhythmia syndromes may serve as a pathogenic basis for autopsy-negative sudden unexplained death in the young (SUDY). However, the contribution of CACNA1C mutations to SUDY is unknown. Objective: We set out to determine the spectrum, prevalence, and pathophysiology of rare CACNA1C variants in SUDY. Methods: Mutational analysis of CACNA1C was conducted in 82 SUDY cases using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Identified variants were engineered using site-directed mutagenesis, and heterologously expressed in TSA-201 or HEK293 cells. Results: Two SUDY cases (2.4%) harbored functional variants in CACNA1C. The E850del and N2091S variants involve highly conserved residues and localize to the II-III linker and C-terminus, respectively. Although observed in publically available exome databases, both variants confer abnormal CaV1.2 electrophysiological characteristics. Examination of the electrophysiological properties revealed the E850del mutation in CACNA1C led to a 95% loss-of-function in ICa, and the N2091S variant led to a 105% gain-of-function in ICa. Additionally, N2091S led to minor kinetic alterations including a −3.4 mV shift in V1/2 of activation. Conclusion: This study provides molecular and functional evidence that rare CACNA1C genetic variants may contribute to the underlying pathogenic basis for some cases of SUDY in either a gain or loss-of-function mechanism.

Original languageEnglish (US)
Pages (from-to)683-692
Number of pages10
JournalCongenital Heart Disease
Issue number6
StatePublished - Nov 1 2016


  • Arrhythmia
  • Genetics
  • Ion Channels
  • Pediatrics
  • Sudden Death

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Surgery
  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine


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