Familial Hypercholesterolemia EVIDENCE FOR A NEWLY RECOGNIZED MUTATION DETERMINING INCREASED FIBROBLAST RECEPTOR AFFINITY BUT DECREASED CAPACITY FOR LOW DENSITY LIPOPROTEIN IN TWO SIBLINGS

from two siblings with classic clinical features of ho-mozygous familial hypercholesterolemia. Plasma cho-lesterol 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 ca-pacity for binding and degradation of '25I-low density lipoprotein (LDL) at 370C was 11 % of normal, con-sistent with the diagnosis of "homozygous LDL re-ceptor-defective " hypercholesterolemia, a disorder in which LDL binding activity is low but detectable. The residual LDL receptor activity was clearly qual-itatively abnormal. The Michaelis constant (Ki) for '25I-LDL was reduced to 20-40 % of normal, indicating a substantially increased affinity for LDL. Increased affinity and reduced capacity for 125I-LDL are also found when normal fibroblasts are assayed at 4°C. As the temperature is raised to 37°C surface LDL binding affinity decreases while capacity increases. At 40C the fibroblasts of our subjects had an affinity for LDL in-distinguishable from normal cells assayed at that tem-perature and a binding capacity 23 % of normal. How-ever, only small changes in affinity and capacity oc-curred upon increasing the temperature to 370C. When 125I-apoprotein E-phospholipid vesicles were bound at 370C the receptor deficiency appeared only half as severe as when '251-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 qual-itatively altered LDL receptors. It is not clear whethe