Haemoglobinopathies Flashcards
What are haemoglobinopathies?
- Genetic disorders of the haemoglobin of RBCs
- Commonest single gene disorders in the world
Structure of Human Haemoglobin
- Tetrameric molecule made up of 2 alpha and 2 beta like globin chains, each chain has a haem group inserted
Human Haemoglobin
Chromosome 16 => Zeta globin chains expressed, then alpha chains expressed in adult life
Chromosome 11 => Epsilon chains expressed then gamma then beta chains expressed in adult life
Haemoglobin Mutations
Structural Variants
- Alterations to protein structure
- Mutation in coding region
- Clinical features depend on site of alteration
Hb S causes Sickle Cell Anaemia => Glu to Val mutation in beta chain at position 6 => molecules in rod like form, cause sickling makes blood viscous and prevents from flowing properly
Single nucleotide change causes single AA change
Types of alterations to protein structure
Clinical disorders caused by structural variants
Thalassaemia Syndromes
- Alterations to globin synthesis
- Either gene deletion or mutation in non coding region
- Hereditary persistance of foetal haemoglobin
Pathophysiology of Thalassaemia
a-thalassaemia
a0 => no alpha chain produced, caused by gross deletion
a+ => reduced level of alpha chain produced, gross deletion or non deletion
Mutations affect:
1) RNA processing
- IVS1 donor splice site
- PolyA signal
2) RNA translation
3)Post-translational stability of mRNA
- Hb Constant Spring
4) Stability of protein
- Hb Quong Sze
b-thalassaemia
b0 => no beta chain produced
b+ => reduced level of beta chain produced
Both not caused by deletion
EB-thalassaemia
- Long Gene deletions in beta cliuster associated with increased HbF levels in adult life
Prevention & Treatment
Prevention:
- Genetic counselling
- Antenatal couselling
Treatment:
Long-term transfusion
Gene therapy
