Fonctions de la protéine ATM et aspects phénotypiques de l'ataxie télangiecatsie.

Abstract

L' ataxie-telangiectasie est une maladie genetique hereditaire rare, caracterisee par une degenerescence cerebelleuse, un deficit immunitaire, une augmentation de la sensibilite aux radiations ionisantes et un risque plus eleve de cancer. Depuis le clonage du gene ATM, en 1995, la recherche sur cette maladie d' expression phenotypique tres pleiotropique s' est beaucoup developpee et les mecanismes moleculaires impliques sont mieux compris. ATM est une proteine-kinase de 350 kDa impliquee dans la detection des cassures double-brin de l' ADN. Des travaux recents ont aussi montre son role dans le controle du cycle cellulaire. Des manifestations cliniques apparaissent directement liees a l' absence de reconnaissance des cassures double-brin. A l' inverse, d' autres aspects cliniques sont plutot le resultat d' une elimination systematique de certaines populations cellulaires en raison d' un controle defaillant du cycle cellulaire. La radiosensibilite clinique extreme en est un exemple. Si l' ensemble des resultats obtenus jusqu' a ce jour permettent effectivement une meilleure comprehension du phenotype clinique, certaines hypotheses demandent a etre confirmees. Des incertitudes persistent concernant la physiopathogenie des telangiectasies ou de la degenerescence des cellules de Purkinje du cervelet.

Ataxia-telangiectasia is a rare hereditary syndrome involving cerebellar degeneration, immunodeficiency, radiosensitivity and increased cancer risk. Since the cloning of the A-T gene, ATM, in 1995, research on this pleiotropic disease and its molecular basis has expanded tremendously. ATM is a 350 kDa kinase protein that appears to be one of the primary sensors of DNA strand-break damage. Recent works showing the interaction of ATM with proteins involved in cell cycle control, and the direct phosphorylation of some of these proteins by ATM, have advanced our understanding of how the loss of a single master regulator of genomic integrity results in this complex disease. Some disease symptoms are direct manifestations of the lack of DNA strand-break recognition. For example the characteristic chromosomal instability and the cancer risk may be a direct result of the abnormal processing of DNA ends. Other are the result of the systematic elimination of cells that have failed to respect cell cycle checkpoints, for example the extreme sensitivity to the lethal effects of irradiation. These hypotheses have to be demonstrated, and some clinical aspects observed in A-T patients remain to be explained, such as the telangiectasia and Purkinje cell degeneration.