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Familial hypercholesterolemia: pathogenesis of a receptor disease
Insights
Familial hypercholesterolemia, a genetic disorder, is characterized by high cholesterol levels due to defective low-density lipoprotein (LDL) receptors. This defect causes cholesterol buildup in scavenger cells, leading to inherited high cholesterol disease.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by defects in receptor molecules.
- It serves as a model for understanding receptor-related diseases.
Purpose of the Study:
- To review evidence explaining the cardinal features of FH.
- To link these features to a genetic defect in the low-density lipoprotein (LDL) receptor.
Main Methods:
- Review of existing scientific literature and evidence.
- Analysis of the three cardinal features of FH in relation to LDL receptor function.
Main Results:
- FH exhibits selective elevation of plasma LDL cholesterol.
- LDL-derived cholesterol is deposited in scavenger cells, not parenchymal cells.
- The condition is inherited as an autosomal dominant trait with gene dosage effects.
Conclusions:
- The cardinal features of FH are explained by a genetic defect in the cell surface LDL receptor.
- Understanding LDL receptor defects is crucial for managing inherited high cholesterol.
Abstract:
Familial hypercholesterolemia is a prototype for a class of diseases that result from defects in receptor molecules. The three cardinal features of familial hypercholesterolemia are: 1) a selective elevation in the plasma level of one cholesterol-carrying lipoprotein, low density lipoprotein (LDL); 2) a selective deposition of LDL-derived cholesterol in macrophage-like scavenger cells throughout the body, but not in parenchymal cells; and 3) inheritance as an autosomal dominant trait with gene dosage effect, i.e., the disease is more serious in patients with the homozygous than with the heterozygous state. In this article, we review the evidence that each of these cardinal features of familial hypercholesterolemia can be explained by a genetic defect in a cell surface receptor for plasma LDL.