Familial hypercholesterolaemia (FH) is most commonly caused by loss-of-function mutations in LDL receptor (LDLR). However, some patients have autosomal dominant hypercholesterolaemia without LDLR mutation. The second most common genetic cause involves gain-of-function mutations in:

• A ApoB (apolipoprotein B, causing familial defective ApoB)
• B CETP (cholesteryl ester transfer protein)
• C Lipoprotein lipase (LPL)
• D PCSK9 (proprotein convertase subtilisin/kexin type 9) ✓

Explanation

PCSK9 is a serine protease secreted by hepatocytes that binds to LDLR on the cell surface and escorts it to lysosomes for degradation rather than allowing receptor recycling. Gain-of-function mutations in PCSK9 cause excessive LDLR degradation, reducing hepatic LDL clearance and causing autosomal dominant hypercholesterolaemia phenotypically identical to heterozygous FH. Conversely, loss-of-function PCSK9 mutations are associated with very low LDL levels and markedly reduced cardiovascular risk. This biology led to the development of PCSK9 inhibitors (evolocumab, alirocumab) as LDL-lowering therapies. Familial defective ApoB (mutant ApoB-100 failing to bind LDLR) is another cause but is less common than PCSK9 GOF mutations in most populations.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.