Question

Question 1:

A) Most FH (Familial hypercholesterolemia) patients have mutations either in the LDL receptor, PCK9 or ApoB. But in theory, a large number of mutations that could impact the endocytic pathway (e.g. mutations in genes involved the budding of endosome vesicles, formation of recycling endosomes, transport of endosomes in the cell, fusion of endosomes with lysosomes, etc.), could impact the level of LDL receptors on the cell surface. Why are these kinds of mutations not commonly identified in FH patients?

B) Statins and PCSK9 inhibitors lower blood cholesterol levels for heterozygous FH patients, but not most homozygous FH patients. Why?

Answer 1

A) Familial hypercholesterolemia is an inherited autosomal dominant disorder. LDL can bind only to LDL receptors on the cell surface which is affected when mutation occur in the gene encoding LDL receptor. But the endocytic pathway is non-specific as it can internalize various types of receptors apart from LDL receptor. Therefore, mutations affecting the endocytic pathway not commonly identified in FH patients.

B) Familial hypercholesterolemia (FH) is an autosomal dominant disorder. Heterozygous FH patients have one dominant and one recessive allele whereas homozygous FH patients have two dominant alleles. The effect of FH is expressed highly in homozygous patients so they do not respond to statins and PCSK9 inhibitors because of lack of normal functioning LDL receptors. But the heterozygous FH patients have 50% normal functioning LDL receptors.