Class 12A: Single gene disorders: defects in receptors and enzymes Flashcards
Mutations in receptors & enzymes
Name some examples of mutations in receptors and mutations in enzymes.
RECEPTOR MUTATIONS
- Familial hypercholesterolaemia
- Lysosomal storage diseases
- Mucolipidosis
ENZYME MUTATIONS
- Niemann Pick Type C disease
- Tay Sachs disease
FH stands for?
And is a mutation of a receptor or enzyme?
Familial hypercholesterolaemia (FH)
It is a receptor mutation
Describe FH.
What is it?
What kind of mutation?
Mode of inheritance?
Due to what kind of factors?
FH stands for familial hypercholesterolaemia.
- concentration of serum cholesterol (LDL) is elevated from birth
- premature coronary heart disease
- mutations in the low density lipoprotein receptor (LDL receptor)
- most common
- autosomal dominant inheritance
- large phenotypic variation
- genetic, metabolic & environmental factors
What are the two clinical forms of FH?
Two clinal forms of FH:
Heterozygous FH (HeFH) - affects 1:500 people --> Higher rates in some populations (Quebec)
Homozygous FH (HoFH) - affects 1:1 million
FH
What is LDL?
Where does it circulate?
a cholesterol carrying molecule
low density lipoprotein
circulates in plasma
FH
Which component in LDL binds to the receptor?
What is its role?
The Apo-B component binds to the LDL-receptor (LDLR)
-required for uptake and breakdown
of the cholesterol components of LDL particles in liver
FH
What is the role of LDLR?
LDL receptor (LDLR) -removes LDL from plasma
- LDLRs interact with LDL via Apo-B and the whole complex undergoes receptor-mediated endocytosis
- LDLs destroyed in lysosomes
- cholesterol released into a cellular pool
- provides a negative feedback loop to maintain levels of LDLRs on the surface of hepatocytes
- increase in cholesterol in pool, decreases number of LDLRs
Mutations in LDL receptor
How many mutations in the LDLR gene?
Over 600 mutations in the LDLR gene have been identified in FH
patients
What is artherosclerosis?
Clogged artery - results from plaque deposits (calcium, cholesterol, other substances) that build up inside the artery and significantly reduce blood flow over time
What is the treatment for artherosclerosis?
Treatment is generally administration of drugs that lower LDL in the
serum
-Statin drugs
What is key to preventing coronary disease?
SCREENING is key to prevent coronary disease
-Counseling on dietary and lifestyle choices
What are LSDs?
Lysosomal storage diseases (LSDs)
A group of genetic disorders that result from the lack of specific lysosomal receptors or enzymes; mostly soluble hydrolases
Each of the 50 known lysosomal hydrolases targets specific substrates
for degradation
LSDs:
~70 genetic disorders
- result in accumulation of non-degraded material in cells
- 2/3 of these diseases have devastating effects on nervous system
- combined frequency of ~ 1:7500
How are proteins sorted to the lysosome normally anyway?
-Note that the lysosome has soluble & membrane proteins
Lysosomal sorting
- The mannose 6 phosphate pathway!
The mannose 6 phosphate independent routes - Ex: sorting by LIMP-2
Describe how lysosomes function in a wild-type cell.
In wild-type cells, most lysosomal hydrolases are transported to lysosomes
by mannose-6-phosphate receptors (M6PRs) that bind their ligands in the
trans-Golgi network (TGN).
Glucocerebrosidase (GC), however, does not
follow the classical M6PR pathway but instead binds to lysosomal integral
membrane protein 2 (LIMP2) in the endoplasmic reticulum (ER), which
directs it to the lysosome
Describe how lysosomes function in a M6PR-deficient cell.
In cells that lack M6PRs (or in I-cell-diseased cells, which lack the phosphotransferase necessary to make the M6P tag), most lysosomal hydrolases are secreted, but GC continues to be targeted to the lysosomes.
