Familial Hypercholesterolemia (FH):
Premature Cardiovascular Risk Reduction
Through Early Action
1
3 Genes Affecting LDL Clearance Can Cause FH
1000+ Mutations Identified to Date
LDL particle
APOB (6 mutations identified)
Codes for production of ligand
protein, ApoB, which connects
LDL particle to receptor
Circulation
Liver cell
LDLR (>1000 mutations) codes for LDL
receptor which binds to ApoB on LDL
particle inducing endocytosis of LDL
PCSK9 (8 GOF mutations identified to date)
codes for PCSK9 enzyme, which degrades the
LDL receptor
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
2
Normally, LDL Receptors on hepatocytes help to
clear LDL Particles from plasma
LDL particle
Circulation
Liver cell
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
3
LDL Receptor (LDLR) Mutations Alter LDL
Receptors, Preventing Attachment to Particle
LDL
particle
ApoB
LDL
receptor
LDL receptor binding site
impaired function prevents
binding to LDL particle
Normal
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
4
FH: LDLR-
PCSK9 Mutations Increase Degradation of LDL
Receptors, Limiting Binding and Endocytosis
LDL
particle
ApoB
LDL
receptor
PCSK9
Normal
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
5
LDL receptors
degraded at a faster
rate by increased
PCSK9 activity
FH: PCSK9+
APOB Mutations Alter Shape of Apo B Ligand on LDL,
Impeding Ability to “Grab” the LDL Receptor
LDL
particle
ApoB
LDL
receptor
Mutation impairs ApoBbinding ability to LDL
receptor
Normal
Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
6
FH: APOB-