Week 4 - Sickle Cell Flashcards
1
Q
What is the structure of normal haemoglobin?
A
adult
- two α goblin chains
- two β goblin chains
- haem group each
- iron in each haem
foetal
- two α goblin chains
- two γ goblin chains
2
Q
What is the HbS mutation?
A
- chromosome 11p
- missense mutation on 6th AA
- GAG to GTG
- glutamine (-ve charge) to valine (uncharged, hydrophobic)
- stiff rod polymer forms
- stretches and elongates cell
- most likely to occur when deoxygenated
3
Q
What are the physiological effects of HbS mutation?
A
- repeated polymerisation
- RBC membrane damaged
- lifespan reduced from 120 to 10-20 days
- vaso-occlusion in narrow vessels
- blockage from cell getting stuck
4
Q
What is sickle cell trait?
A
- carriers
- HbAS
- no symptoms
- situations (dehydration, low O2) can cause sickling
- advantage of protection against malaria symptoms
5
Q
What is HbC?
A
- variant in the same locus
- example of compound heterozygosity if with sickle cell
- because it affects same gene
- missense mutation
- from glutamic acid to lysine (AAG)
- HbSC has milder SCD symptoms
6
Q
What are the possible gene therapies for SCD?
A
- improve abnormal β globin
- or restore γ globin expressions
- by gene addition of either
- or gene editing
- to correct/modify β globin
- or up-regulate γ globin
- target haematopoietic stem cells
7
Q
How is ex-vivo gene therapy done?
A
- HSC release stimulated
- collected by apheresis
- gene modified in culture
- reinfusion by myeloablative chemotherapy
- high dose required
- can kill off remaining bona marrow and ovaries
- risk of cancer and infertility
8
Q
What are the strategies for gene addition?
A
- gene of interest in lentiviral vector
- βA-T87Q globin changes 87th AA from T to Q
- βAS3 globin has anti-sickling properties to inhibit remaining sickling
- γ goblin
9
Q
How can γ- globin be upregulated?
A
- BCL11A shuts off its production after fetal development
- CRISPR-Cas9 can disrupt it to restore γ globin production
