HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA - FAILURE OF NORMAL ALLELE TO COMPENSATE FOR MUTANT ALLELE AT A REGULATED GENETIC-LOCUS

In normal human fibroblasts, the synthesis of a cell surface receptor for plasma low density lipoprotein (LDL) is regulated by a sensitive system of feedback suppression. The number of functional LDL receptors declines by more than 20-fold when cellular stores of esterified cholesterol are increased by incubation of cells with an exogenous source of cholesterol. Fibroblasts from patients with the heterozygous form of familial hypercholesterolemia (FH) possess 1 functional allele and 1 nonfunctional allele at the LDL receptor locus. The effect that this deficiency produces upon the pattern of regulation of the single functional allele at the LDL receptor locus was studied. Under growth conditions that induced a maximal rate of LDL receptor synthesis (i.e., growth in the absence of an exogenous source of cholesterol), the FH heterozygote cells produced about 1/2 as many functional LDL receptors as did the normal cells. When grown in the presence of increasing amounts of exogenous cholesterol, the FH heterozygote and normal cells suppressed their respective LDL receptor activities in parallel. Over a wide range of LDL receptor activities, at each level of cellular esterified cholesterol, the FH heterozygote cells expressed about 1/2 as many receptors as did the normal cells. In the FH heterozygote cells, the receptor regulatory mechanism dictates that the normal allele produces only the amount of gene product that it would normally produce at a given level of cellular esterified cholesterol. The failure of the regulatory mechanism to stimulate the normal allele at the LDL receptor locus to produce twice its normal amount of gene product leaves the FH heterozygote cells with a persistent 50% deficiency in LDL receptors under all cell growth conditions.