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Contenu archivé le 2024-04-30

From molecular biology to clinical management: a novel approach for the long qt syndrome

Objectif

The major goals of our project are:
1) to extend the clinical knowledge of LQTS by establishing for the first time the clinical features of each form of LQTS based on genetic characterization of the different families;
2) to identify, or clarify, the genetic abnormalities in LQTS and assess their electrophysiologic equivalents both in expression systems and in tissue samples from affected individuals;
3) to develop in vitro models reproducing the specific electrophysiologic defect of the different forms of LQTS in order to have an experimental setting in which new therapeutic approaches could be tested and
4) to identify and test targeted and individualized therapies for the various affected families according to the specific ionic abnormality present in their members.

The long QT syndrome is an inherited disorder that causes abnormal prolongation of ventricular repolarization (clinically measured as a prolongation of the QT interval on the electrocardiogram) and is associated with the frequent occurrence of life-threatening ventricular tachyarrhythmias that eventually lead to the sudden death of most affected and not properly treated patients. Linkage analysis has allowed the identification of four chromosomes linked to the disease (chromosomes number 3,4,7,11). Since LQTS is a relatively rare condition, a transnational collaboration is necessary for the concentration of a multidisciplinary research project. The present project has a multinational organization and is multidisciplinary, as each country involved will have both clinical and molecular biological expertise in order to provide a comprehensive functional unit. Yet all data will be entirely shared in order to avoid time consuming errors in pursuing wrong directions of investigations.

Three major levels of research are foreseen:
1) clinical identification of large families suitable for genetic studies and their phenotypic characterization;
2) blood samples will be obtained from affected and non affected family members and molecular genetic evaluation of DNA will be performed by means of linkage analysis; search for mutations in the human genes considered candidates for LQT will be also performed by using single-strand conformation polymorphism analysis;
3) whenever genes are identified, expression in oocytes will allow evaluation of the functional alteration resulting from the mutation, with analysis of the single channels that might be involved; at the same time, electrophysiologic evaluation with microelectrodes of biopsy samples from the ventricles of affected patients will allow to compare the electrophysiologic alterations seen in the expression systems to those present in the tissue from affected individuals.

It is important to remember that most of these patients are children and teenagers whose chances of having a normal life depends entirely on being properly diagnosed and properly treated. The results from the present research project will be of benefit to the citizens of the European Community, thus fulfilling one of the major tasks of the BIOMED 2 projects. This is particularly true if we consider that only implementation of transnational collaboration supported by dedicated funding will make possible to collect the number of cases adequate to provide the answers to the pressing questions outlined above and initiate an unprecedented European effort to solve the riddle of LQTS.

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IRCCS POLICLINICO SAN MATTEO - ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO
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