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Homozygous familial hypercholesterolemia mutant with a defect in internalization of low density lipoprotein
Abstract:
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.
Insights
Researchers identified a unique cell line from a familial hypercholesterolemia (FH) patient that binds low-density lipoprotein (LDL) but cannot internalize it. This discovery confirms a homozygous defect in LDL internalization, previously only theorized.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels.
- Homozygous FH patients typically exhibit severe defects in low-density lipoprotein (LDL) metabolism.
- Previous research predicted a homozygous state for LDL internalization defects.
Purpose of the Study:
- To characterize a unique fibroblast cell line derived from a homozygous FH patient.
- To investigate the mechanism of LDL binding and internalization in this cell line.
- To confirm the hereditary nature of the LDL internalization defect.
Main Methods:
- Cell culture of fibroblasts from FH patients and their families.
- Analysis of LDL binding kinetics and specificity.
- Assessment of cholesterol synthesis regulation.
- Evaluation of LDL receptor-mediated internalization.
Main Results:
- The unique fibroblast line bound LDL normally or even at higher levels.
- This cell line failed to regulate cholesterol synthesis, characteristic of homozygous FH.
- Internalization of receptor-bound LDL was completely absent in this cell line.
- The defect was confirmed to be hereditary, with the subject being a pure homozygote.
Conclusions:
- This study presents the first confirmed case of a pure homozygous defect in LDL internalization.
- The findings validate previous predictions regarding the homozygous state of this specific FH defect.
- The cell line provides a valuable model for studying LDL receptor function and FH pathogenesis.