Low density lipoprotein metabolism in cultured fibroblasts from a new group of patients presenting clinically with homozygous familial hypercholesterolemia.

The metabolism of low density lipoproteins (LDL) was studied in cultured fibroblasts obtained from five local patients diagnosed, on the basis of clinical features and serum cholesterol concentrations, as having the homozygous form of familial hypercholesterolemia. LDL receptor function was assessed by measuring the binding, internalization, and degradation of 125I-labeled LDL, and by measuring the stimulation of cellular acyl-CoA cholesterol acyltransferase (ACAT) activity which followed exposure to LDL. Fibroblasts from two cases (CF and GM) showed receptor activities which were approximately 10% of the values obtained with normal cells, while ACAT stimulation by LDL was very low. These two patients were classified as homozygous for a receptor-defective abnormality. However, fibroblasts from the other three patients (JG, ES, and TT) showed greater than 25% of normal receptor activity, as assessed by 125I-LDL binding and catabolism. ACAT stimulation by LDL in cells from JG and ES was within the range of values shown by cells previously characterized as heterozygous for a receptor-negative mutation. Cells from ES behaved atypically: a low, but nonsaturable, activation by LDL was evident. ACAT stimulation by LDL was normal in cells from TT. Receptor activities of the cells from the available parents, assessed on the basis of LDL binding and degradation or of ACAT stimulation, were not clearly distinguishable from those of normal cells. These results add to the growing evidence of genetic heterogeneity underlying the clinical picture associated with familial hypercholesterolemia in different geographical distributions.