FAMILIAL HYPERCHOLESTEROLEMIA 25 YEARS AF TER .1. LDL RECEPTOR DEFECTS

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, Ther coined the di sorder familial hypercholesterolemia (FH). Fourteen years later T. Inn erarity and co-workers showed that the disease was genetically heterog eneous since It was also associated with defects in the gene coding fo r apo B. This new molecular entity was called familial defective apoli poprotein B-100 (FDB). Since the initial work of Brown and Goldstein, the LDL receptor gene (LDLR) has been cloned and 316 mutations have be en identified in FH probands. Only 25 % of these are major rearrangeme nts often involving unequal crossing overs between the many repetitive Alu elements of the gene. The computerized analysis of the 220 point mutations contained in our LDLR-database shows that these are mostly p rivate and missense. Unexpectedly, only 17% of the mutations occurred in CpG dinucleotides. Although the mutations are widely distributed th roughout the gene, there is a significant excess of mutations identifi ed within exon 4 that encodes three of the seven repeats of the ligand -binding domain. Mutations mostly affect the conserved amino acids loc ated in the COOH-terminal regions of the repeats. The cloning of the L DLR gene and its systematic sequencing has also revealed 39 sequence p olymorphisms. Only two of these are multiallelic and most display stro ng linkage disequilibrium. Concurrently, animal models of FH have been identified in which the Watanabe-heritable-hyperlipidemic (WHHL) rabb it is currently the most important. A non-human primate model of FH ha s been established recently after the identification of a non-sense mu tation in the LDLR gene in a family of rhesus monkey. By employing tra nsgenic technology, a mouse strain in which the human LDLR gene was in troduced has indicates 0that 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 h as developed xanthomas and aortic atherosclerosis only after a very ri ch lipid diet, Recently, a study of ex vivo gene therapy for homozygou s FH was demonstrated its feasibility in humans. All the five patients enrolled for this experiment of liver-directed gene therapy have tole rated the procedure well without significant complications, and have s hown a persistent transgene expression lasting at least four months af ter 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.