Familial hypercholesterolemia. Evidence for a newly recognized mutation determining increased fibroblast receptor affinity but decreased capacity for low density lipoprotein in two siblings.

Cultured skin fibroblasts were obtained from two siblings with classic clinical features of homozygous familial hypercholesterolemia. Plasma cholesterol values were 970 and 802 mg/100 ml in the siblings, 332 mg/100 ml in the mother, and 426 mg/100 ml in the father. Fibroblast receptor-specific capacity for binding and degradation of (125)I-low density lipoprotein (LDL) at 37 degrees C was 11% of normal, consistent with the diagnosis of "homozygous LDL receptor-defective" hypercholesterolemia, a disorder in which LDL binding activity is low but detectable. The residual LDL receptor activity was clearly qualitatively abnormal. The Michaelis constant (K(m)) for (125)I-LDL was reduced to 20-40% of normal, indicating a substantially increased affinity for LDL. Increased affinity and reduced capacity for (125)I-LDL are also found when normal fibroblasts are assayed at 4 degrees C. As the temperature is raised to 37 degrees C surface LDL binding affinity decreases while capacity increases. At 4 degrees C the fibroblasts of our subjects had an affinity for LDL indistinguishable from normal cells assayed at that temperature and a binding capacity 23% of normal. However, only small changes in affinity and capacity occurred upon increasing the temperature to 37 degrees C. When (125)I-apoprotein E-phospholipid vesicles were bound at 37 degrees C the receptor deficiency appeared only half as severe as when (125)I-LDL was used as ligand.A family study suggests that the siblings are genetic compounds rather than homozygotes, having inherited a mutant maternal gene causing absent or silent LDL receptors and a mutant paternal gene resulting in qualitatively altered LDL receptors. It is not clear whether these defects are present at the same or different genetic loci. The altered receptors are characterized by increased affinity and moderately reduced capacity for LDL at 37 degrees C and are accompanied by hypercholesterolemia at least as severe as that associated with familial hypercholesterolemia with absent or nonfunctional LDL receptors.