Modulation polygénique des maladies monogéniques : l'exemple de la drépanocytose

Abstract

La drépanocytose résulte d'une mutation unique et son mécanisme physiopathologique a été minutieusement exploré ; elle constitue donc un modèle de choix pour aborder le problème de la variabilité d'expression clinique des maladies monogéniques. Peuvent être la cible de phénomènes modificateurs : ( 1) la polymérisation de l'hémoglobine S (diminuée par l'hémoglobine foetale) ; (2) la concentration intra- érythrocytaire en hémoglobine S, si existe une a-thalassémie concomitante, ou une modification de l'action de facteurs tramrégulateurs sur l'expression respective des gènes foetaux r-globine et du gène adulte ps-globine; (3) le profil particulier d'expression de protéines autres que l'hémoglobine dans les réticulocytes de drépanocytaires, car la drépanocytose est aussi une maladie cellulaire et rhéologique : anomalies des constituants de la membrane érythrocytaire et de sa perméabilité, phénomènes d'adhérence aux parois vasculaires, activation de la cascade de la coagulation, sont tous des processus faisant intervenir des protéines partenaires qui sont, ou pourraient être, polymorphes.

Variability in the clinical expression of many monogenic diseases has always been very puzzling. Because sickle cell anemia results from a single mutation, and because its pathophysiological mechanism has been thoroughly investigated, it constitutes a model of choice to investigate this issue and can bring already some informative clues. Three features of the pathophysiological scheme can be the target of modifying phenomena: the process of hemoglobin S (Hb S) polymerization, the intraerythrocytic concentration of Hb S, and an expression profile of proteins, other than hemoglobin, specific to reticulocytes in sicklers. Factors that can modify each of these three features have been characterized. (1) Polymerization can be hindered by other hemoglobins, mainly fetal hemoglobin (Hb F). (2) Intraerythrocytic concentration of Hb S is decreased by a coinherited alpha-thalassemia or by a modulation of the action of transacting factors on the respective expression of the fetal gamma-genes vs the adult beta-gene. (3) Sickle cell anemia has also been defined as a cellular and theological disease, various mechanisms of which have been studied: membrane modifications, increased adhesion to the vascular endothelium, activation of the coagulation cascade. All these processes involve partner proteins that are or could be polymorphic. Genes coding for these proteins can be located in cis from the beta(S) gene or in trans on other chromosomes. Their combined action can be described as the polygenic control of this monogenic disease.