FH

Question 1

Gene location for FH

Answer 1

19p13.2, codes for LDL-R

Question 2

LDL-R protein is

Answer 2

839 amino acids that exist in the phospholipid bilayer of various cells

Question 3

5 functional domains and is involved in

Answer 3

regulating the concentration of LDL proteins that circulate in blood plasma

Question 4

ApoB-100 forms a ligand receptor complex with LDLR allowing

Answer 4

LDL to endocytose into the target cell which is bound to LDLR by the N-terminus

Question 5

LDL is required for

Answer 5

synthesis of cell membrane and steroid hormones

Question 6

PCSK9 degrades

Answer 6

LDLR

Question 7

Gain of function mutations reduce

Answer 7

Abundance of LDLRs on the cell surface and lead to accumulation of LDL in plasma

Question 8

Accumulation of LDL in plasma is associated with

Answer 8

High CVD risk

Question 9

FH can result in

Answer 9

Atherosclerosis

Question 10

Atherosclerosis ..

Answer 10

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

Question 11

Xanthomas

Answer 11

build up of cholesterol in skin

Question 12

Xanthelasmas

Answer 12

form around eye, common in homozygous FH

Question 13

Xanthomas can cause

Answer 13

movement issues as deposits can build up in tendons

Question 14

5 types of mutational classes, 6th discovered by

Answer 14

Strom et al 2015

Question 15

Mutations cause

Answer 15

Changes in the receptor activity that means cholesterol levels increase beyond the normal range

Question 16

Class I mutation

Answer 16

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

Question 17

Class II mutation

Answer 17

Leads to defective receptor translocation from the ER to cell surface (mutations in exons 2-14)

Question 18

Class III mutation

Answer 18

Causes LDLR to have defective binding to ApoB-100 to the N-terminus of the receptor (exons 2-14)

Question 19

Class IV mutation

Answer 19

Defective endocytosis of LDLR-LDL complex in the clathrin pits (exons 16-18)

Question 20

Class V mutation

Answer 20

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)

Question 21

Class VI mutation

Answer 21

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

Question 22

Class VI differs from class II that

Answer 22

focusses on ER translocation