RT-135
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From genotype to phenotype. The
case of the long QT syndrome
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Peter J. Schwartz.
Cattedra di Cardiologia, Universita degli Studi di Pavia, Dipartimento di
Cardiologia, Policlinico S. Matteo IRCCS, Pavia, Italy
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Abstract
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During the last few years several of the genes
responsible for the long QT syndrome (LQTS) have been identified. These findings
stimulated a widespread interest for the disease, involving molecular biologists and
clinical cardiologists, for quite specific reasons. One is that all the LQTS genes
identified so far encode for ionic channels involved in the control of ventricular
repolarization. Another is that the expression of the mutated genes and the ensuing
electrophysiologic studies have allowed to understand the mechanisms by which specific
mutations are able to prolong action potential duration by selective alterations in the
inactivation of the inward Na+ current or in the activation of two of the major
repolarizing K+ currents.
The affected patients appear to have rather specific responses to interventions
targeted toward the correction of the electrophysiologic consequences of their mutations.
For instance, the patients with mutations on SCN5A, the cardiac sodium channel gene,
respond with a significant shortening of the QT interval to mexiletine. Also, the ability
to shorten the QT interval in response to heart rate increases, as they occur during
exercise, varies according to the current affected by the various mutations. Finally, the
circumstances involved in the onset of the syncopes and cardiac arrests of these patients
vary in their frequency according to the genes involved. These ongoing observations will
impact on the clinical management of the gene-carriers.
The long QT syndrome appears to be a unique model for the study of how tight can be
the genotype-phenotype relation and represents a direct bridge between molecular biology
and clinical cardiology.
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Key Words
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Arrhytmhogenesis
long QT syndrome, controle of ventricular repolarization, gene disease, genotype,
phenotype, OA
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