Toth - Figure 8 - Genetic etiologies
Other than abnormalities in LDL receptor structure and function, other etiologies for a
defective FH phenotype include:
- Mutations in the gene for ApoB100, referred to as familial defective apoB; the
most common mutation giving rise to a loss of functionality in apoB occurs
from a substitution mutation at amino acid position 3500, resulting in a dramatic
reduction of the LDL receptor affinity for apoB, thus compromising the ability
of an LDL particle to bind to the receptor and its cholesterol taken up into the
hepatocyte cytosol.
- Autosomal dominant hypercholesterolemia, which is attributable to a gain of
function mutation in the gene for PCSK9 (proprotein convertase subtilisin-like
lexin type 9), a protein that regulates the half-life of expression of the LDL
receptor. If there is a gain-of-function mutation in the gene, this accelerates the
entry of the LDL receptor toward the endosomal compartment, where the LDL
receptor is destroyed; on the other hand, loss-of-function mutations in PCSK9
can be associated with very dramatic reductions in LDL cholesterol; patients with
loss-of-function mutations experience quite significant reductions in lifetime
risk for CAD and in the case of homozygous mutations, patients may have
lifelong LDL cholesterol levels <20 mg/dL and remain remarkably resistant to
development of atherosclerotic disease.
- Deficiency of 7-alpha hydroxylase; the enzyme 7-alpha hydroxylase catalyzes the
rate-limiting step for the conversion of cholesterol into bile acids; in the case of
genetic 7-alpha hydroxylase deficiency, the intracellular concentration of LDL
is very high and this leads to a reduction in the expression of LDL receptors
on the hepatocyte surface and an impaired capacity to clear systemic LDL
cholesterol, resulting in marked elevations in LDL cholesterol and increased risk
for premature CAD.
- Autosomal recessive hypercholesterolemia, a very important condition that is due
to reduced expression of an adaptor protein that facilitates the association of the
LDL receptor with clathrin in cell surface coated pits.
Toth PP.
J Clin Lipidol.
2011; 5(6).
