L'hypercholestérolémie familiale 25 ans après.II- Formes non-liées au récepteur des LDL

Abstract

L’hypercholestérolémie familiale fut d’abord rapportée à une altération du récepteur des LDL. Mais, trois ans après la première description d’une mutation de son gène (LDLR), l’hypothèse qu’un déficit de son ligand, l’apolipoprotéine B-100, pouvait produire un phénotype clinico-biochimique similaire à celui de l’hypercholestérolémie familiale allait être confirmée. A ce jour, trois mutations ponctuelles du gène APOB, ont été associées à cette nouvelle entité moléculaire, la déficience familiale en apolipoprotéine B-100. Des défauts combinés des gènes APOB et LDLR ont également été identifiés. Enfin, différents travaux actuels démontrent que d’autres gènes doivent contribuer au phénotype d’hypercholestérolémie familiale.

Fourteen years after the identification of the LDL receptor and the demonstration that its defects account for familial hypercholesterolemia (FH), the hypothesis that a defect in its ligand, apolipoprotein B-100 (apo B-100) could also account for FH was confirmed. Innerarity et al. identified the R3500Q mutation in the APOB gene and showed that it significantly affected the affinity of LDL for the receptor. Thus, genetic heterogeneity was demonstrated and the new molecular entity was called familial defective apolipoprotein B-100 (FDB). Great clinical and biological variability was reported between heterozygotes for the FDB-R3500Q mutation. Paradoxically, all homozygotes for this mutation displayed a clinical and biological presentation markedly comparable to that of heterozygotes. Double heterozygosity for mutations in the LDLR and the APOB genes was also identified. The probands presented with an intermediate phenotype between heterozygous FDB and homozygous FH. The FDB-R3500Q mutation is mostly found in populations of European descent and is carried by a unique ten-marker haplotype of the APOB gene, therefore demonstrating that it is carried by an unique European ancestral chromosome. Finally, the prevalence of the R3500Q mutation was shown to be as high as 1/500 but variable among populations and could be associated with an European north-south gradient. Allelic heterogeneity was also demonstrated in FDB. Two other C [right arrow] T transitions were identified resulting in the substitution of an arginine residue in the binding domain of apo B-100 (mutations R3531C and R3500W). The R3531C mutation is less frequent than the R3500Q mutation but also seems to be carried by an unique European ancestral chromosome. At present, no animal models of FDB have been identified or obtained through transgenesis. Finally, the results of various functional and genetic studies clearly demonstrate that defects in other major genes are involved in dominant as well as in recessive familial hypercholesterolemia. [References: 40]