L'hypercholestérolémie familiale 25 ans après.I- Défauts du récepteur des LDL

Abstract

L’hypercholestérolémie est un facteur de risque majeur d’athérosclérose, problème important de santé publique des pays industrialisés. Elle touche un sujet sur 20 dans nos sociétés, et son traitement est l’une des priorités de la lutte contre les maladies cardiovasculaires. En 1973, Michael Brown et Joseph Goldstein associaient des anomalies du récepteur LDL à une hypercholestérolémie à transmission autosomique dominante : la FH (familial hypercholesterolemia). Quatorze ans plus tard, l’équipe de Thomas Innerarity montrait l’hétérogénéité génétique de cette affection en identifiant une mutation dans l’apolipoprotéine B, ligand spécifique du récepteur LDL. Cette nouvelle maladie, la FDB (familial defective apolipoprotein B-100), est cliniquement indiscernable de la FH. Depuis les travaux initiaux de Brown et Goldstein, le gène codant pour le récepteur LDL a été cloné et, actuellement, plus de 300 mutations ont été identifiées. Les premières expériences de thérapie génique ont été réalisées chez des sujets homozygotes pour la FH.

In 1973 M. Brown and J. Goldstein demonstrated that autosomal dominant type IIa familial hypercholesterolemia results from mutations in the cell surface receptor that removes LDL from plasma. They coined the disorder familial hypercholesterolemia (FH). Fourteen years later T. Innerarity and co-workers showed that the disease was genetically heterogeneous since it was also associated with defects in the gene coding for apo B. This new molecular entity was called familial defective apolipoprotein B-100 (FDB). Since the initial work of Brown and Goldstein, the LDL receptor gene (LDLR) has been cloned and 316 mutations have been identified in FH probands. Only 25% of these are major rearrangements often involving unequal crossing-overs between the many repetitive Alu elements of tile gene. The computerized analysis of the 220 point mutations contained in our LDLR-database shows that these are mostly private and missense. Unexpectedly, only 17% of the mutations occurred in CpG dinucleotides. Although the mutations are widely distributed throughout the gene, there is a significant excess of mutations identified within exon 4 that encodes three of the seven repeats of the ligand-binding domain. Mutations mostly affect the conserved amino acids located in the COOH-terminal regions of the repeats. The cloning of the LDLR gene and its systematic sequencing has also revealed 39 sequence polymorphisms. Only two of these are multiallelic and most display strong linkage disequilibrium. Concurrently, animal models of FH have been identified in which the Watanabe-heritable-hyperlipidemic (WHHL) rabbit is currently the most important. A non-human primate model of FH has been established recently after the identification of a non-sense mutation in the LDLR gene in a family of rhesus monkeys. By employing transgenic technology, a mouse strain in which the human LDLR gene was introduced has indicated that in mice the unregulated overexpression of LDL receptors can protect against diet-induced hypercholesterolemia. A mouse strain homozygous for a targeted disruption of the LDLR gene has developed xanthomas and aortic atherosclerosis only after a very rich lipid diet. Recently, a study of ex vivo gene therapy for homozygous FH has demonstrated its feasibility in humans. All the five patients enrolled for this experiment of liver-directed gene therapy have tolerated the procedure well without significant complications and have shown a persistent transgene expression lasting at least four months after gene therapy. Three of these patients had significant decreases in total cholesterol, LDL and apo B levels, and one of them showed a 53% increase of the in vivo LDL catabolism. [References: 40]