Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death

Abstract

BACKGROUND L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. OBJECTIVE The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. METHODS/RESULTS Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. CONCLUSION The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Cav genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…By screening 162 probands with BrS or BrS combined with short QT syndrome (SQTS) (BrS+ SQTS), there were 7 newly identified mutations in CACNA1C , including p.E1115K, p.R1880Q, p.V2014I, p.D2130N, p.E1829_Q1833dup, p.C1873Y and p.E850del [102]. Functionally, Ca V 1.2 channel with p.E1115K had a reduced calcium influx.…”

“…p.V2014I mutation in Ca V 1.2 channel reduced peak current density and shifted half-inactivation voltage to more negative potentials, whereas voltage at the maximum peak current remained unchanged. In another mutation, the duplication of five amino acids in exon 43 of CACNA1C (p.E1829_Q1833dup) resulted in nearly compete suppression of calcium current ( I Ca ) [102]. These loss-of-function mutations may help to explain the shortening of QT interval and other features of ECG.…”

“…A patient with BrS, who has a p.V2014I mutation in CACNA1C , also had a p.D601E polymorphism in CACNB2b , and this polymorphism dramatically augmented the late calcium current of LTCC, which prolonged the QT interval, the modulatory effect of this single nucleotide polymorphism probably interprets the fact that QTc in this proband is not associated with SQTS [102]. Other mutations were also identified [102,106], including p.S143F and p.T450I, which were reported in the prevailing BrS-associated variants of NHLBI GO Exome Sequencing Project population [107].…”

“…Other mutations were also identified [102,106], including p.S143F and p.T450I, which were reported in the prevailing BrS-associated variants of NHLBI GO Exome Sequencing Project population [107]. However, the functions of these mutations on the Ca V β 2 subunit remain unknown.…”

“…It has been found 3 different missense mutations in CACNA2D1 (p.S709N, p.D550Y, and p.Q917H) in 3 BrS patients from a cohort made up of 205 patients with BrS [102]. Among these mutations, p.S709N and p.Q917H were also identified in Exome Sequencing Project population by Risgaard et al [107].…”