A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.

Jessica A Hennessey,Ronald Kanter,Hector Barajas-Martinez,David J Tester,Nicole J Boczek,Yong-Hui Jiang,Joelle D Miller,William Patrick,Ryan Pfeiffer,Charles Antzelevitch,Brittan S Sutphin,Michael J Ackerman,Geoffrey S Pitt,Tuck Wah Soong

doi:10.1371/journal.pone.0106982

Abstract

Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on CaV1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of CACNA1C (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of CaV1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of CaV1.2. We also observed a negative shift of V1/2 of activation and positive shift of V1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on CaV1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the CACNA1C variant to diminish voltage-dependent inactivation of CaV1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of CaV1.2 can contribute to QT prolongation.

Highlights

Few arrhythmogenic mutations in CACNA1C, which encodes the pore-forming a1C subunit of the CaV1.2 L-type Ca2+ channel have been reported in long QT syndrome (LQTS), an inherited or acquired arrhythmia characterized by an abnormally long electrocardiographic QT interval, which reflects an underlying prolonged ventricular cardiomyocyte action potential caused by the specific biophysical consequences of the underlying mutation
Because sudden unexpected infant death (SUID) has been linked to mutations in LQTS loci–and associated with S1103Y [11,12], suggesting that physiologic or metabolic changes in the context of a pro-arrhythmic variant may increase the risk for life-threatening events–we looked for the presence of this variant among a SUIDS cohort, in which the p.G1911R variant was subsequently identified in an additional subject
We describe a child with a prolonged QTC interval, lifethreatening arrhythmias, seizures, developmental delay, microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis

Summary

Introduction

Few arrhythmogenic mutations in CACNA1C, which encodes the pore-forming a1C subunit of the CaV1.2 L-type Ca2+ channel have been reported in long QT syndrome (LQTS), an inherited or acquired arrhythmia characterized by an abnormally long electrocardiographic QT interval, which reflects an underlying prolonged ventricular cardiomyocyte action potential caused by the specific biophysical consequences of the underlying mutation.Much more common are mutations in K+ channels and Na+ channels [1,2], reported almost a decade before Ca2+ channel arrhythmia mutations were first described in Timothy Syndrome (TS, OMIM #601005, long QT syndrome 8). Few arrhythmogenic mutations in CACNA1C, which encodes the pore-forming a1C subunit of the CaV1.2 L-type Ca2+ channel have been reported in long QT syndrome (LQTS), an inherited or acquired arrhythmia characterized by an abnormally long electrocardiographic QT interval, which reflects an underlying prolonged ventricular cardiomyocyte action potential caused by the specific biophysical consequences of the underlying mutation. Functional characterization of p.G406R revealed a marked reduction in voltage-dependent inactivation (VDI); the consequent increase in Ca2+ influx prolongs the cardiac action potential, and the QT interval, and can generate early afterdepolarizations capable of triggering life-threatening arrhythmias [3,4,5]. A variant of TS (denoted TS2) was identified in two patients who had either a G406R mutation or a G402S mutation in the predominant exon 8 and who presented with a subset of the phenotypes found in the original TS cohort [4]. Like the G406R mutation in the exon 8a, the G406R/G402S mutations in exon 8 diminish VDI [4]

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