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EP News: Basic and Translational Penelope A. Boyden, PhD From the Department of Pharmacology, Columbia University, New York, New York.
There is more to sarcoplasmic/endoplasmic reticulum Ca2þ homeostasis than ryanodine receptors Trimeric intracellular cation channels (TRICs) represent a novel class of cation channels. Two isoforms are in human and mouse genomes. TRIC-A is expressed in the muscle sarcoplasmic reticulum (SR), while TRIC-B is ubiquitously expressed in the endoplasmic reticulum (ER). Ablation of either leads to compromised Kþ permeation and Ca2þ release across SR/ER membranes. Thus, TRICs provide a counterbalancing Kþ flux that reduces SR/ ER membrane depolarization needed for the maintenance of electrochemical gradients. TRIC-A and TRIC-B differ in function of cell Ca2þ signaling. Tric-a(/) mice display defective Ca2þ sparks and spontaneous transient outward currents in smooth muscle and develop hypertension. Knockout of TRIC-B results in abnormal IP3-mediated Ca2þ release in airway epithelial cells, respiratory defects, and neonatal lethality. Tric-a(/) and Tric-b(þ/) mice are susceptible to stress-induced heart failure. TRIC-A directly modulates the function of RyR2 Ca2þ release channel. The authors (Zhou et al, Circ Res XXXX;XX:XX, PMID 24526676) conclude that TRICs, in addition to providing a countercurrent for SR Ca2þ release, function as modulators of RyR2/IP3 receptor channels.
A mutation in CALM1-encoding calmodulin in familial VF in childhood and adolescence Marsman et al (J Am Coll Cardiol XXXX;XX:XX, PMID24076290) identified the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood/ adolescence. Sudden cardiac death in young individuals presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important since IVF does not manifest with clinical abnormalities. Exome sequencing was performed in 2 family members who had been resuscitated from cardiac arrest. This family presented with a history of VF and sudden cardiac death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at ages 9 and10 years, and another 2 had documented VF at 10 and 16 years. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1-encoding calmodulin. This mutation was carried by 1 sibling who died suddenly as well as by the mother and another sibling, both asymptomatic but displaying a prolonged QT interval. The authors conclude that a mutation in CALM1 can underlie IVF in childhood and adolescence. The causality of the Address reprint requests and correspondence: Dr Penelope A. Boyden, Department of Pharmacology, Columbia University, New York, NY 10032. E-mail address: [email protected].
mutation is supported by studies in which residue F90 mediates the direct interaction of CaM with target peptides.
Brugada phenotype explained in apparently benign sodium channel mutations Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A. Typically, BrS mutations in SCN5A result in a reduction of Na current because of a dominantnegative effect on wild-type (WT) channels. A category of apparently benign (“atypical”) BrS SCN5A mutations in vitro demonstrate minor biophysical defects. It is not clear how these mutations produce a BrS phenotype. Hoshi et al (Circ Cardiovasc Genet XXXX;XX:XX, PMID 24573164) hypothesized that atypical mutations lead to reduced Na currents when coexpressed with WT mutations to mimic the heterozygous patient genotype. WT and “atypical” BrS mutations coexpressed in HEK293 cells showed a reduction in Na current densities similar to that by typical BrS mutations. Reduced Na current was also seen when the atypical mutations were expressed in human cardiomyocytes. Thus, benign BrS mutations in SCN5A lead to the electrocardiographic abnormalities seen in patients with BrS through an induced defect that is only present when the mutations are coexpressed with WT channels. Their work has implications for risk management and stratification for some patients with SCN5A-implicated BrS.
Exome sequencing and increased burden of rare K channel variants in the risk of drug-induced long QT syndrome Weeke et al (J Am Coll Cardiol XXXX;XX:XX, PMID 24561134) determined whether rare variants are associated with drug-induced long QT syndrome (diLQTS). Here whole exome sequencing on 65 diLQTS cases and 148 drug-exposed controls of European descent was done. Rare variant analyses (variable threshold and sequence kernel association test) and gene set analyses helped to identify genes enriched with rare amino acid coding variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS to 515 ethnically matched controls from the Exome Sequencing Project. Rare variants in 7 genes were enriched in diLQTS cases according to sequence kernel association test or variable threshold compared with drugexposed controls. Of these, they replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project controls. Thirty-seven percent of the diLQTS cases also had Z1 rare acid amino coding variant as compared with 21% controls. Thus, by combining whole exome sequencing with aggregated rare variant analyses, the authors implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS.
1547-5271/$-see front matter B 2014 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
http://dx.doi.org/10.1016/j.hrthm.2014.04.008
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EP News: Basic and Translational Penelope A. Boyden, PhD From the Department of Pharmacology, Columbia University, New York, New York.
There is more to sarcoplasmic/endoplasmic reticulum Ca2þ homeostasis than ryanodine receptors Trimeric intracellular cation channels (TRICs) represent a novel class of cation channels. Two isoforms are in human and mouse genomes. TRIC-A is expressed in the muscle sarcoplasmic reticulum (SR), while TRIC-B is ubiquitously expressed in the endoplasmic reticulum (ER). Ablation of either leads to compromised Kþ permeation and Ca2þ release across SR/ER membranes. Thus, TRICs provide a counterbalancing Kþ flux that reduces SR/ ER membrane depolarization needed for the maintenance of electrochemical gradients. TRIC-A and TRIC-B differ in function of cell Ca2þ signaling. Tric-a(/) mice display defective Ca2þ sparks and spontaneous transient outward currents in smooth muscle and develop hypertension. Knockout of TRIC-B results in abnormal IP3-mediated Ca2þ release in airway epithelial cells, respiratory defects, and neonatal lethality. Tric-a(/) and Tric-b(þ/) mice are susceptible to stress-induced heart failure. TRIC-A directly modulates the function of RyR2 Ca2þ release channel. The authors (Zhou et al, Circ Res XXXX;XX:XX, PMID 24526676) conclude that TRICs, in addition to providing a countercurrent for SR Ca2þ release, function as modulators of RyR2/IP3 receptor channels.
A mutation in CALM1-encoding calmodulin in familial VF in childhood and adolescence Marsman et al (J Am Coll Cardiol XXXX;XX:XX, PMID24076290) identified the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood/ adolescence. Sudden cardiac death in young individuals presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important since IVF does not manifest with clinical abnormalities. Exome sequencing was performed in 2 family members who had been resuscitated from cardiac arrest. This family presented with a history of VF and sudden cardiac death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at ages 9 and10 years, and another 2 had documented VF at 10 and 16 years. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1-encoding calmodulin. This mutation was carried by 1 sibling who died suddenly as well as by the mother and another sibling, both asymptomatic but displaying a prolonged QT interval. The authors conclude that a mutation in CALM1 can underlie IVF in childhood and adolescence. The causality of the Address reprint requests and correspondence: Dr Penelope A. Boyden, Department of Pharmacology, Columbia University, New York, NY 10032. E-mail address: [email protected].
mutation is supported by studies in which residue F90 mediates the direct interaction of CaM with target peptides.
Brugada phenotype explained in apparently benign sodium channel mutations Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A. Typically, BrS mutations in SCN5A result in a reduction of Na current because of a dominantnegative effect on wild-type (WT) channels. A category of apparently benign (“atypical”) BrS SCN5A mutations in vitro demonstrate minor biophysical defects. It is not clear how these mutations produce a BrS phenotype. Hoshi et al (Circ Cardiovasc Genet XXXX;XX:XX, PMID 24573164) hypothesized that atypical mutations lead to reduced Na currents when coexpressed with WT mutations to mimic the heterozygous patient genotype. WT and “atypical” BrS mutations coexpressed in HEK293 cells showed a reduction in Na current densities similar to that by typical BrS mutations. Reduced Na current was also seen when the atypical mutations were expressed in human cardiomyocytes. Thus, benign BrS mutations in SCN5A lead to the electrocardiographic abnormalities seen in patients with BrS through an induced defect that is only present when the mutations are coexpressed with WT channels. Their work has implications for risk management and stratification for some patients with SCN5A-implicated BrS.
Exome sequencing and increased burden of rare K channel variants in the risk of drug-induced long QT syndrome Weeke et al (J Am Coll Cardiol XXXX;XX:XX, PMID 24561134) determined whether rare variants are associated with drug-induced long QT syndrome (diLQTS). Here whole exome sequencing on 65 diLQTS cases and 148 drug-exposed controls of European descent was done. Rare variant analyses (variable threshold and sequence kernel association test) and gene set analyses helped to identify genes enriched with rare amino acid coding variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS to 515 ethnically matched controls from the Exome Sequencing Project. Rare variants in 7 genes were enriched in diLQTS cases according to sequence kernel association test or variable threshold compared with drugexposed controls. Of these, they replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project controls. Thirty-seven percent of the diLQTS cases also had Z1 rare acid amino coding variant as compared with 21% controls. Thus, by combining whole exome sequencing with aggregated rare variant analyses, the authors implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS.
1547-5271/$-see front matter B 2014 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
http://dx.doi.org/10.1016/j.hrthm.2014.04.008
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