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Functional characterization of CaV?2? mutations associated with sudden cardiac death.

ABSTRACT: L-type Ca(2+) channels play a critical role in cardiac rhythmicity. These ion channels are oligomeric complexes formed by the pore-forming CaV?1 with the auxiliary CaV? and CaV?2? subunits. CaV?2? increases the peak current density and improves the voltage-dependent activation gating of CaV1.2 channels without increasing the surface expression of the CaV?1 subunit. The functional impact of genetic variants of CACNA2D1 (the gene encoding for CaV?2?), associated with shorter repolarization QT intervals (the time interval between the Q and the T waves on the cardiac electrocardiogram), was investigated after recombinant expression of the full complement of L-type CaV1.2 subunits in human embryonic kidney 293 cells. By performing side-by-side high resolution flow cytometry assays and whole-cell patch clamp recordings, we revealed that the surface density of the CaV?2? wild-type protein correlates with the peak current density. Furthermore, the cell surface density of CaV?2? mutants S755T, Q917H, and S956T was not significantly different from the cell surface density of the CaV?2? wild-type protein expressed under the same conditions. In contrast, the cell surface expression of CaV?2? D550Y, CaV?2? S709N, and the double mutant D550Y/Q917H was reduced, respectively, by ?30-33% for the single mutants and by 60% for the latter. The cell surface density of D550Y/Q917H was more significantly impaired than protein stability, suggesting that surface trafficking of CaV?2? was disrupted by the double mutation. Co-expression with D550Y/Q917H significantly decreased CaV1.2 currents as compared with results obtained with CaV?2? wild type. It is concluded that D550Y/Q917H reduced inward Ca(2+) currents through a defect in the cell surface trafficking of CaV?2?. Altogether, our results provide novel insight in the molecular mechanism underlying the modulation of CaV1.2 currents by CaV?2?.

SUBMITTER: Bourdin B

PROVIDER: S-EPMC4317020 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Functional characterization of CaVα2δ mutations associated with sudden cardiac death.

Bourdin Benoîte B Shakeri Behzad B Tétreault Marie-Philippe MP Sauvé Rémy R Lesage Sylvie S Parent Lucie L

The Journal of biological chemistry 20141219 5

L-type Ca(2+) channels play a critical role in cardiac rhythmicity. These ion channels are oligomeric complexes formed by the pore-forming CaVα1 with the auxiliary CaVβ and CaVα2δ subunits. CaVα2δ increases the peak current density and improves the voltage-dependent activation gating of CaV1.2 channels without increasing the surface expression of the CaVα1 subunit. The functional impact of genetic variants of CACNA2D1 (the gene encoding for CaVα2δ), associated with shorter repolarization QT inte ...[more]

PMID: 25527503

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Project description:BACKGROUND:Sudden cardiac death occurs in ?220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES:This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS:The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS:Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS:Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ?1% of asymptomatic adults.

Dataset Information

Functional characterization of CaV?2? mutations associated with sudden cardiac death.

Publications

Functional characterization of CaVα2δ mutations associated with sudden cardiac death.

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