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- Title
Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young.
- Authors
Sutphin, Brittan S.; Boczek, Nicole J.; Barajas‐Martínez, Héctor; Hu, Dan; Ye, Dan; Tester, David J.; Antzelevitch, Charles; Ackerman, Michael J.
- Abstract
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.
- Subjects
SUDDEN death in children; AUTOPSY; CALCIUM channels; VOLTAGE-gated ion channels; PATHOLOGICAL physiology; ELECTROPHYSIOLOGY
- Publication
Congenital Heart Disease, 2016, Vol 11, Issue 6, p683
- ISSN
1747-079X
- Publication type
Article
- DOI
10.1111/chd.12371