Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by a raised concentrati on of LDL in plasma that results in a significantly increased risk of prema ture atherosclerosis. In FH, impaired removal of LDL from the circulation r esults from inherited mutations in the LDL receptor gene or, more rarely, i n the gene for apo B, the ligand for the LDL receptor. We have identified t wo unrelated clinically homozygous FH patients whose cells exhibit no measu rable degradation of LDL in culture. Extensive analysis of DNA and mRNA rev ealed no defect in the LDL receptor, and alleles of the LDL receptor or apo B genes do not cosegregate with hypercholesterolemia in these families. FA GS(R) analysis of binding and uptake of fluorescent LDL or anti-LDL recepto r antibodies showed that LDL receptors are on the cell surface and bind LDL normally, but fail to be internalized, suggesting that some component of e ndocytosis through clathrin-coated pits is defective. Internalization of th e transferrin receptor occurs normally, suggesting that the defective gene product may interact specifically with the LDL receptor internalization sig nal. Identification of the defective gene will aid genetic diagnosis of oth er hypercholesterolemic patients and elucidate the mechanism by which LDL r eceptors are internalized.