11- BSC Genetic Inheritance Flashcards
In FH what receptor is defective
LDLR
LDL cholesterol not taken up
What apo protein is in soluble LDL?
ApoB100 or ApoE
Apo is transport system which results in change of a product within a compartment
LDL receptor
What domains do they contain
Cell surface glycoprotein in liver cells, coded form gene LDLR
Has N terminal ligand binding domain- extracellular
Membrane spanning domain
C-terminal cytoplasmic domain
- Contains FxNPxY internalization protein
- interacts with ARH (LDLR adaptor protein) to allow clathrin on inside so when endocytose it will be coated in clathrin.
LDLR internalization
ApoB100 serves as ligand > binds to LDLR receptor > endocytosed as clathrin coated vessicle
Can recycle receptors back to membrane or
fuse with lysosome > endolysosome > degradation to AA (protease) and free cholesterol (cholesterol ester hydrolase)
What will free cholesterol do in the cell
inhibit HMG CoA reductase (synthesizes cholesterol)
–sterol sensing domain activates degradation of enzyme by proteasome
Stored as cholesterol esters
– enzymes: acyl CoA, cholesterol acyl transferase, cholesterol esterification for stroage
Shut down synthesis of receptors by transcription factors
Low levels of cholesterol in the cell. What will happen?
- stimulate HMG CoA reductase to synthesize chol.
2. Turn genes on to make receptors for membrane
SRE
Sterol-sensitive Response Element
promoters of genes involved in cholesterol biosynthesis and internalization
SREBP
Sterol Regulating Element Binding Proteins
Transcription factors
SREBP cleavage activating protein (SCAP)
on ER membrane
detects free cholesterol
cleaves SREBP
Change gene expression.
Allelic Heterogeneity
Mix of different genes for one allele.
ex. 900 different mutations in gene that causes FH
FH heterozygotes
50% of LDLR expression
2x increase in plasma LDL
Xanthomas and artherosclerosis in adult life
FH homozygous
Almost no LDLR expression
6x increase in plasma LDL
Xanthomas and artherosclerosis in adolescence
Lethal by age 30
What is happening in FH?
defect in transport of LDL into cell.
Cell synthesizes LDL (HMG CoA reductase)
Increase in LDLR synthesis (SREBPs)
Class I mutation
No synthesis of LDLR
no receptors
Class 2 mutation
folding problem
accumulates in ER
