Disease Related with LDL receptor Disfunction

Familial Hypercholesterolemia (FH) is a congenital disorder of cholesterol metabolism in which the level of cholesterol rises. The discovery of this disease dates to the 18 hundred BC.  Later, the discovery lead to the homozygous and heterozygous form of FH.  Almost it took a decade, they found a relationship that the hallmark of this disease is the increase level of LDL.  Further on the LDL receptor discovery and the deficits in LDL receptor caused by mutation, leading to lower amount of LDL receptor turnover and decreased activity of LDL receptor, were the culprits responsible for increase level of LDL in the blood.

LDL Receptor Structure domains and their functions

LDL receptor is a bio-membrane mosaic receptor containing 839 amino acids with subdivision of five sub domains.  Included are Ligand binding domain which is extracellular and bind with apoB and apoE of LDL and VLDL respectively. The EGF precursor homology domain attached next to the ligand binding domain is also responsible for the VLDL and LDL attachment and control the release and recycling of the LDL receptor to the cell surface. The O-linked binding domain next is just outside the plasma membrane stretches out the ligand molecule and provide ease in binding to LDL-R.  Membrane spinning domain is the next which anchor the LDL receptor in the plasma membrane and cause its spinning. The last domain of LDL receptor is cytoplasmic domain which function is to direct the LDL-Rs to the coated pits and clustering in these pits. Mutations in LDL-Receptor which is responsible for internalization of LDL can lead to consequences of FH.  Point mutations which cases defects in LDL-Rs are:

1)    Class 1: In this type of mutation the receptor or precursor protein synthesis is absent subsequently increasing the level of LDL causing hypercholesterolemia..

2)    Class 2: In this class of mutation there occur defects like absent or impaired formation of LDL-Rs. The normal routing of LDL-R receptor is very slow or completed blockage of the LDL protein to Leave Endoplasmic Reticulum.

3)    Class 3:  In class three mutation the defects of synthesis and transport of LDL are intact, but the binding domain is mutated and cause impaired LDL binding to the receptor.    

4)    Class 4: In class four mutation the clustering ability of the LDL receptors and further on internalization to the cell vanishes.

5)    Class 5: No receptor recycling and rapid degradation caused by mutation in EGFP-H domain. 

6)    Class 6: Mutation in cytoplasmic domain causing receptors failing to be targeted to membrane.