FAMILIAL HYPERCHOLESTEROLEMIA 25 YEARS AF TER .2. FORMS WITH NORMAL LDL RECEPTOR

Fourteen years after the identification of the LDL receptor and the de monstration that its defects account for familial hypercholesterolemia (FH), the hypothesis that a defect in its ligand, apolipoprotein B-10 0 (apo B-100) could also account for FH was confirmed. Innerarity et n l, identified the R3500Q mutation in the APOB gene and showed that it significantly affected the affinity of LDL, for the receptor. Thus, ge netic heterogeneity was demonstrated and the new molecular entity was called familial defective apolipoprotein B-100 (FDB). Great clinical a nd biological variability was reported between heterozygotes for the F DB-R3500Q mutation. Paradoxically, all homozygotes for this mutation d isplayed a clinical and biological presentation markedly comparable to that of heteroxygotes. Double heterozygosity for mutations in the LDL R 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 des cent and is carried by a unique ten-marker haplotype of the APOB gene, therefore demonstrating that it is carried by an unique European ance stral chromosome. Finally, the prevalence of the R3500Q mutation was s hown to be as high as 1/500 but variable among populations and could b e associated with an European north-south gradient. Allelic heterogene ity was also demonstrated in FDB. Two other C --> T transitions were i dentified 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 b e carried by an unique European ancestral chromosome. At present, no a nimal models of FDB have been identified or obtained through transgene sis. Finally, the results of various functional and genetic studies cl early demonstrate that defects in other major genes are involved in do minant as well as in recessive familial hypercholesterolemia.