Coinheritance of two mild defects in low density lipoprotein receptor function produces severe hypercholesterolemia

A family is described in which the probands, twin girls, had severe hypercholesterolemia suggestive of familial hypercholesterolemia (FH). The mother of the twins had normal plasma cholesterol levels, and the father had only moderate hypercholesterolemia. Moreover, low density lipoprotein (LDL) binding studies in cultured fibroblasts and isolated lymphocytes in the parents failed to reveal significantly reduced LDL receptor activity that is typical of FH heterozygotes. Turnover studies of LDL in the parents, however, revealed low fractional clearance rates (FCRs) for LDL. In cultured fibroblasts and isolated lymphocytes from the twin probands, binding of normal LDL was half normal or less. LDL turnover studies in the twins revealed a marked reduction in FCRs for LDL. When the twins were treated with lovastatin, however, FCRs for LDL increased significantly, suggesting enhancement of LDL receptor activity. This finding along with LDL binding studies in the cultured cells infer that the twins did not have homozygous FH. In addition, all family members tested negative for familial defective apolipoprotein-B-100, and LDL isolated from the mother and twins showed normal binding to normal fibroblasts. The overall data suggest that the severe hypercholesterolemia in the offspring was due to inheritance of mild to moderate defects of LDL receptor function from both parents. Although the latter defects could not be detected with certainty by in vitro tests in each parent, they were evident from LDL turnover tests. Coinheritance of these defects apparently produced severe hypercholesterolemia in the offspring.