Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

Abstract

Background-Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Methods and Results-Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca v␤2b ), CACNA2D1 (Ca v␣2␦1 ), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca v 1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals Յ360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the ␣ 1 -and ␤ 2b -subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca v 1.2 channels but normal trafficking of channels containing G490R Ca v 1.2 or S481L Ca v␤2b -subunits. Conclusions-This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals. Key Words: arrhythmia Ⅲ genetics Ⅲ electrophysiology Ⅲ tachycardia Ⅲ fibrillation C ardiac arrhythmias are responsible for an estimated 1 million cases of syncope and sudden cardiac death (SCD) among Europeans and Americans each year. 1 Cardiac arrhythmias can be acquired as a consequence of coronary heart disease or may be secondary to familial or inherited syndromes. The past decade has witnessed an explosion of information linking cardiac ion channel mutations with a wide variety of inherited arrhythmia syndromes. 2 The long-QT syndrome has been associated with 10 different Clinical Perspective p 449genes, in large part owing to the pioneering studies of Keating and coworkers. The LQT8 form of long-QT syndrome, also known as Timothy syndrome, is associated with gain-offunction mutations in cardiac calcium channel activity. 3,4 The cardiac L-type calcium channel is a protein complex formed by at least 3 subunits, ␣ 1 , ␤, and ␣ 2␦ . The pore-forming Ca v 1. subunit, encoded by CACNB2b, modulates calcium channel activity in the human heart and enables trafficking by suppressing an endoplasmic reticulum retention signal in the I-II loop of the ␣ 1 -subunit. 5 The short-QT syndrome (SQTS), a clinical entity first described in 2000,6 has been associated ...

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

“…Of note, Myoscape-deficient female mice also reveal a significant shortening of the QT interval. In humans, this phenotype has been associated with loss of function mutations of the LTCC alpha-subunit encoding CACNA1C gene42, further supporting the concept that the findings in myoscape-deficient mice can be explained by LTCC impairment. Interestingly, one of these mutations (A39V) also led to reduced membrane localization of the LTCC42.…”

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

“…Human short QT syndrome is diagnosed using the J point to T peak interval that may represent the interval between the end of the ventricular complex to the peak of the repolarisation wave 48. Short QT syndrome has been traced to HERG and other K + channel mutations and more recently, Ca 2+ channel function 49. The present findings are thus consistent with reported alterations in K + conductance properties in the Pgc‐1 β −/− system that would also modify current‐load matching 15.…”

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

“…A male European descent with BrS and a shortened QTc interval showed a heterozygous mutation in exon 2 of the CACNA1C gene, which made a p.A39V substitution, near the N-terminus within a highly conserved region of the Ca V α 1C [98]. In another case, a male Turkish patient with BrS and a shortened QT interval, was detected a novel heterozygous mutation in exon 10 of the CACNA1C gene was predicted to result in a p.G490R substitution in I-II loop [98].…”

“…No.Amino acid changeNucleotide changeExonLocationMutation typeGain/loss of functionMain effects on LTCCDiagnosisReferencesMutations in CACNA1C 1p.A28Tc.82 G > A2N-terminusMissenseGain I Ca,L ↑, positively shift of V 0.5,inact LQT8Wemhoner et al 2015 82 2p.A39Vc.116 C > T2N-terminusMissenseLoss I Ca,L ↓, LTCC trafficking ↓BrS3/SQT4Antzelevitch et al 2007 98 3p.P381Sc.1141 C > T8ADI-S6Missense-N.S.LQT8Fukuyama et al 2014 88 4p.G402Sp.G406Rc.1204 G > Ac.1216 G > A8DI-S6MissenseGainVDI ↓TS2Splawski et al 2005 62 5p.G406Rc.1216 G > A8ADI-S6MissenseGainVDI ↓↓, CDI ↑TS1Splawski et al 2004 61 ;Barrett et al 2008 66 6p.M456Ic.1368 G > A9I-II loopMissense-N.S.LQT8…”