Homozygous familial hypercholesterolemia mutant with a defect in internalization of low density lipoprotein.

During studies on binding of low density lipoprotein (LDL) to fibroblasts from patients with the homozygous form of familial hypercholesterolemia (FH), a unique line was derived from subject M.N. This line could bind as much LDL as normal cells, or even more. However, like fibroblasts from other patients with the homozygous form of FH, it failed to show regulation of cholesterol synthesis. Analyses of the LDL receptors showed that this line could not mediate internalization of receptor-bound LDL. Studies on the fibroblasts of the parents of this subject showed that the inability to internalize LDL was hereditary and that the subject was a pure homozygote for this defect. The plausibility of this finding was supported by the fact that her parents were first cousins. The possible existence of a homozygous state of this defect was predicted by Goldstein et al. [Goldstein, J. L., Brown, M. S. & Stone, N. J. (1977) Cell 12, 629-41], but an actual case of the internalization defect in a pure homozygous form had not been found. There were no differences from normal cells in the nature of the LDL binding activity of this line, such as in its specificity, affinity, or Ca2+ requirement.