MOLECULAR-GENETICS OF PURE PRIMARY HYPERCHOLESTEROLEMIA

Pure primary hypercholesterolemia include a set of lipid disorders related to the metabolism of Low Density Lipoproteins (LDL), which are now recognised as causes of atherosclerosis. Although many genetic and environmental factors contribute to their pathogenesis, two major genes influence LDL metabolism : the LDL receptor and its natural ligand, apolipoprotein B. These genes have been characterised and localised on human chromosomes, and can be studied at the molecular level. The many gene defects observed on both these loci as causes of primary hypercholesterolemia, have demonstrated the genetic heterogeneity of these disorders (one phenotype related to different predisposing loci). The candidate gene approach, is a method that can overcome the difficulties of this genetic heterogeneity. Using simplified molecular techniques it can be used in predictive diagnosis, pointing the predisposing locus, leading to the identification of causative mutations and guiding therapeutic strategies. Hence, new inborn errors of metabolism for which the molecular basis is well defined are now recognised, delineating the remaining defects to be characterised that also underlie primary hypercholesterolemia. These disorders account for the most frequent monogenic disorders in the French population. A better knowledge of their influence among other predisposing causes of atherosclerosis, will help define new preventive strategies based on the genetic component to its predisposition.