Genetics and sudden cardiac death

  • F. Luft
  • Published 2001 in Journal of Molecular Medicine

Abstract

event. Woody Allen is quoted as having said that, “sudden death is nature’s way of telling you to slow down.” Major disturbances of cardiac rhythm, ventricular fibrillation, tachyarrhythmias, bradyarrhythmias, and asystole, account for more than half of deaths related to myocardial ischemia and myocardial infarction [1,2]. Furthermore, at least half of patients with cardiac failure die suddenly. Most of the deaths from hypertrophic or dilatative cardiomyopathy are related to sudden death. Compelling evidence supports the notion that the “sudden infant death syndrome” or crib death is a sudden cardiac death. The causes of sudden cardiac death are extremely diverse, but all eventually influence the heart’s electrical performance. Mendelian inherited causes of sudden cardiac death have been identified, the so-called long QT syndromes, that by virtue of gene mapping and cloning techniques, have shed a great deal of light on the mechanisms of lethal arrhythmia. A graphic representation of the cardiomyocyte action potential and its relationship to the standard electrocardiogram is shown in Fig. 1. In this issue of the Journal of Molecular Medicine Schulze-Bahr and colleagues [3] report on a novel long QT 5 gene mutation. The authors studied the human minK gene. minK and the long QT 1 gene (KvLQT1) product form a native cardiac K+ channel that regulates the slow delayed rectifier potassium current IKs. Schulze-Bahr et al. investigated 150 unrelated persons with inherited long QT syndrome and performed single-stranded conformational polymorphism analysis of the minK gene. They identified a family with heterozygous single-nucleotide polymorphism at nt 325 (G325A) that results in an amino acid substitution from valine to isoleucine in the C terminus of the protein at codon 109 (V1091). Expression studies of V1091 minK were then performed in Xenopus oocytes with subsequent voltage clamp analysis. The mutated subunit resulted in a reduction in the current to about one-third compared to control values. Since only one of two mutation carriers in the family met electrocardiographic criteria of long QT syndrome, the authors reason that the phenotype is mild. Possibly, that individual is at risk when ingesting QT interval-prolonging drugs or if heart disease supervenes. Excellent reviews of Mendelian long QT syndromes are available [4,5]. Long QT 1 involves a dominant-negative or loss of function mutation of KvLQT1. KvLQT1 and minK coassemble to form cardiac IKs potassium channels. KvLQT1 encodes the voltage-gated α-subunit. MinK codes for 129 amino acids and coassembles with the alpha subunit. MinK alone can be expressed in Xenopus oocytes, since Xenopus possesses a homolog of KvLQT1 that permits formation of a potassium current. HERG encodes the α-subunit of cardiac IKr which is responsible for termination of the action potential plateau phase. MiRP1, or minK-related protein 1, has homology to minK. When expressed together with HERG in heterologous systems, the resultant current closely resembles IKr in cardiac myocytes. Thus HERG α-subunits assemble with MiRP1 β-subunits to form cardiac IKr channels. SCN5A encodes the α-subunit of sodium channels responsible for the initial cardiac action potential (phase 0). Mutations in SCN5A encode for a portion of the protein involved in channel inactivation. Mutant channels depolarize normally and inactivate but can reopen during the plateau phase. SCN5A mutations cause long QT syndrome but can also cause familial ventricular fibrillation. RyR2 encodes the calcium release channel, the so-called ryanodine receptor. RyR2 channels are activated by calcium that triggers the channels to release more calcium from the sarcoplasmic reticulum. The identified missense mutations probably lead to calcium overload, a substrate for ventricular arrhythmia. Thus, all known ventricular arrhythmia-susceptibility genes encode cardiac ion channels. SCN5A encodes sodium channels that initiate the action potential. HERG encodes α-subunits that assemble with MiRP1 β-subunits to form cardiac IKr potassium channels. KVLQT1 assembles with minK to form IKs potassium channels. IKr and IKr are responsible for termination of the plateau phase and contribute to the final repolarization. RyR2 encodes the ryGenetics and sudden cardiac death J Mol Med (2001) 79:477–479 © Springer-Verlag 2001 DOI 10.1007/s001090100262

DOI: 10.1007/s001090100262

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Cite this paper

@article{Luft2001GeneticsAS, title={Genetics and sudden cardiac death}, author={F. Luft}, journal={Journal of Molecular Medicine}, year={2001}, volume={79}, pages={477-479} }