FH Flashcards
Gene location for FH
19p13.2, codes for LDL-R
LDL-R protein is
839 amino acids that exist in the phospholipid bilayer of various cells
5 functional domains and is involved in
regulating the concentration of LDL proteins that circulate in blood plasma
ApoB-100 forms a ligand receptor complex with LDLR allowing
LDL to endocytose into the target cell which is bound to LDLR by the N-terminus
LDL is required for
synthesis of cell membrane and steroid hormones
PCSK9 degrades
LDLR
Gain of function mutations reduce
Abundance of LDLRs on the cell surface and lead to accumulation of LDL in plasma
Accumulation of LDL in plasma is associated with
High CVD risk
FH can result in
Atherosclerosis
Atherosclerosis ..
LDL becomes oxidised attracting leukocytes (especially macrophages) to the endothelium
Macrophages engulf LDLs forming foam cells which increases the deposition of collagen within plaques causing it to harden
Foam cells die forming fatty streak
Plaque ruptures leading to thrombosis forming a blood clot that can cause HA or stroke
Xanthomas
build up of cholesterol in skin
Xanthelasmas
form around eye, common in homozygous FH
Xanthomas can cause
movement issues as deposits can build up in tendons
5 types of mutational classes, 6th discovered by
Strom et al 2015
Mutations cause
Changes in the receptor activity that means cholesterol levels increase beyond the normal range
Class I mutation
Results in non-functional receptor that occurs in the promotor region of the receptor and synthesis of the receptor in the ER doesnt occur
Most serious type of mutation
Class II mutation
Leads to defective receptor translocation from the ER to cell surface (mutations in exons 2-14)
Class III mutation
Causes LDLR to have defective binding to ApoB-100 to the N-terminus of the receptor (exons 2-14)
Class IV mutation
Defective endocytosis of LDLR-LDL complex in the clathrin pits (exons 16-18)
Class V mutation
Results in defective recycling of LDLR due to the receptor not releasing from the ligand and so it undergoes proteolysis rather than being returned to cell surface (exon 7-14)
Class VI mutation
Newly proposed by Stom et al 2015
Insertion of basic residue within the hydrophobic core of the TMD that prevents recognition and integration of the LDLR into the cell membrane
Class VI differs from class II that
focusses on ER translocation
