Cardiology>>>>>Hyperlipidemia
Question 2#

Phenotypic presentation of FH has been demonstrated to be caused by various mutations associated with all but one of the following:

A. Defects in the hepatic LDL receptor (LDL-R)
B. Defects in apolipoprotein B (apoB)
C. Loss-of-function mutation of PCSK9
D. Loss-of-function mutation of LDLRAP1

Correct Answer is D

Comment:

LDLRAP1 mediates internalization of LDL-C via clathrin-coated pits, and loss-of-function mutations would decrease LDL-C clearance. Defects in apolipoprotein B (apoB). The LDL-R on the hepatocyte binds to apoB (acts as ligand, binding LDL particle to receptor) on the LDL particle inducing internalization via clathrin-coated pits (mediated by LDLRAP1) and endocytosis of the complex. Defects in the receptor itself or the apoB molecule may reduce LDL-C clearance. The protein PCSK9 can bind to the LDL/LDL-R complex and when internalized prevents recycling of the LDLR to the hepatocyte surface. A gain in function mutation of PCSK9 (by further reducing recycling of LDL-Rs) has been shown to be associated with increase in LDL-C and CVD.