Question

A 30-year old patient comes into the ER after suffering from a massive coronary heart attack. After genetic analysis, it is determined that he suffers from familial hypercholesterolemia. Using what you know about the LDL receptor pathway and clathrin mediated endocytosis specifically, explain ONE area in that pathway that could be defective and how it would cause the disease phenotype. *Specifically describe the defect in the clathrin mechanism, don't go into the genetics that's just the background for the question*

Answer 1

The LDL receptor is very much important for the clathrin mediated endocytosis of LDL Cholesterol by human cells. Cholesteryl ester molecules are marked by ApoB protein. This ApopB-LDL Cholesterol complex is then recognised by LDL receptor which initiates the endocytosis process. LDL receptors cluster into clathrin-coated vesicles via membrane invagination. These vesicles are then fused with endosomes which releases LDL receptor and digests the LDL cholesterol and ApoB protein into fatty acids and amino acids. The released LDL receptor is then recycled back to the membrane.

Familial hypercholesterolemia is caused by mutation in the gene encoding LDL receptor.

Any defect (mutation) in ApoB can also lead to familial hypercholesterolemia.

So, due to lack of LDL receptor (in familial hypercholesterolemia), LDL's level is increased in the blood leading to atherosclerosis and other coronary heart diseases.