Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol.

The homozygous form of the autosomal dominant disorder, familial hypercholesterolemia, is characterized by the presence in children of profound hypercholesterolemia, cutaneous planar xanthomas, and rapidly progressive coronary vascular disease that usually results in death before age 30 years. Cultured skin fibroblasts from three unrelated subjects with this disorder showed 40- to 60-fold higher activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34), the rate-controlling enzyme in cholesterol biosynthesis, when compared with fibroblasts of seven control subjects. Enhanced enzyme activity resulted from a complete absence of normal feedback suppression by low-density lipoproteins, which led to a marked overproduction of cholesterol by the mutant cells. The demonstration of apparently identical kinetic properties of the reductase activity of control and mutant cells, coupled with the evidence that this enzyme is normally regulated not by allosteric effectors but by alterations in enzyme synthesis and degradation, suggests that the primary genetic abnormality does not involve the structural gene for the enzyme itself, but a hitherto unidentified gene whose product is necessary for mediation of feedback control by lipoproteins. The fibroblasts of two obligate heterozygotes, the parents of one of the homozygotes, showed a pattern of enzyme regulation intermediate between that of controls and homozygotes.