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[Molecular genetics in the hereditary form of long QT syndrome]

L Georgijević Milić

Med. Pregl., 2000 Jan-Feb , 53, 51-4

INTRODUCTION: Progress in molecular genetics contributed to the discovery of pathophysiologic mechanisms of hereditary diseases as well as better diagnostics and efficient therapy. Several defective ge- nes have been discovered on different chromosomes (3,4,7,11 and 21 pair of chromosomes), and also their relationship with some types of LQTS (long QT syndrome). Gene dysfunction leads to the dysfunction of ion channels, which consequently causes prolonged duration of repolarization in cardiac muscle. These changes are manifested on electrocardiogram with prolonged duration of QT interval (over 0.44 sec.). Familial forms of LQTS are inherited as autosomal dominant (Roman Ward syndrome) and autosomal recessive (Jervell Lange-Neilsen syndrome). The final form of LQTS is defined even with hearing loss. Clinical survey: malignant ventricular arrhythmia, syncope and sudden death. MOLECULAR ARCHITECTURE OF VOLTAGE-GATED ION CHANNELS: Duration of voltage-gated ion can be regulated by Na and K channels. Cardiac action potential plateau is an indicator of the balance of inward and outward ionic currents. During this process of voltage-gated potential two currents are activated: depolarized inward current (it happens in the Na channels) and repolarized outward current (it happens in the K channels). Na channels are polypeptides incorporated in cell membrane. Their main function is to control excitability in myocardial cell. They consist of two subunits: alpha and beta. Class Ib of anty-arrhythmics (Lidocaine, Mexiletine and Tocainide) as well as Diphenylhydantoin blocks Na channels in the state of inactivation, in fact, during the depolarization of the cell. For controlling the cardiac voltage-gated potential the most important are voltage-sensitive K channels. For appearance of K ions delayed refraction of K channels (Kv) is of importance. Depending on the velocity of activation, Kv are divided into two groups: channels with rapid activation (Kvr) and channels with slow activation (Kvs). By activation of these delayed rectification channels (Kv) beta agonists shorten the action potential of the heart. GENETIC ASPECTS OF LQTS: Five loci which are connected with Romano Ward's familial form of LQTS have been described up to now. Specific mutant gene is responsible for function of K channels and it is located on short branch (part) of the 11-th pair of chromosome 11p15.5 (KVLQT-LQT1), long branch of the 7-th pair of chromosomes 7q35-36 (K- HERG-LQT2), as well as on the 21-st pair of chromosome (KCNE1-LQT5). Defective gene which is responsible for the function of Na channels is located on the short branch of chromosome 3p21-24 (SCN5A-LQT3). The gene which is located on the long branch of the 4-th pair of chromosome 4q25-27 (LQT4) has not been examined sufficiently. Persons with Jevell Lange-Neilsen syndrome inherit pathological allele from both parents (KvLQT1 or LQT5-minK). CONNECTION BETWEEN ION CHANNELS AND GENE MUTATION: Among all genes which are responsible for LQTS the most examined one is the so-called HERG gene located on the 7-th pair of chromosome (LQT2). Mutation of this gene leads to reduction in strength of outward K currents or to the dysfunction of K channel proteins. Mutant gene causes so-called missense mutation, in fact wrong change of amino acid in the protein chain. Among all described LQTS the most frequent and the most malignant form is LQT1. In 99% cases psychophysical stress can cause arrhythmia, syncope or sudden death. LQT3 and LQT5 are very rare. CONCLUSION: Genetic screening in LQTS patients provides discovery of risk population which demands anti-arrhythmic therapy with beta-blockers. A lot of arguments speak in favour of genetic screening in cases with LQTS. It is considered that if the diagnosis is known, genetic testing is not necessary, but it is useful. Moreover, it is obligatory in symptomatic cases as well as in those with suspected diagnosis of LQTS.