Globin Genes Flashcards
% of world population who are carriers for haemoglobin disorders?
5%
What is the general structure of haemoglobin?
Tetrameric protein: 2 alpha-like + 2 beta-like chains. 4 haem groups, each with an iron atom
How many molecules of oxygen can 1 Hb carry?
4 (1 for each haem group)
What are the embryonic haemoglobins?
Hb Gower 1 ζ2ε2, Hb Gower α2ε2, Hb Portland ζ2γ2
What is the foetal haemoglobin?
HbF α2γ2
What are the adult haemoglobins?
HbA α2β2, HbA2 α2δ2
Which Globin is the most important from foetus to adult?
Alpha globin as it is present in all haemoglobins
How are Globin genes arranged?
In clusters on chromosome 16, 11 (see if there are more)
Are all globin genes functional?
No, some are non-functional and are remnants of evolution
How many alpha and beta Globin genes are there in the diploid genome?
4 alpha
2 beta
What % of chains are affected in 1 beta-gene variant & 1 alpha-gene variant respectively?
50% beta
~25% alpha
S+S of sickle cell disease?
Abnormally shaped (sickled) RBCs, fingers of unequal and abnormal length, bony infarctions of phalanges and metacarpals MI, stroke, ulcers, heart failure
How does sickle cell disease lead to stroke?
Deoxygenated HbS forms roads and deforms cells -> sickled cells block capillaries (can’t squeeze through) -> MI
What is the treatment for sickle cell disease?
Folic acid (improve RBC production)
Antibiotics (fight infections)
Analgesia (combat pain of crises)
Hydroxyurea (reduce crises)
Kidney transplant and gallbladder removal
Wound care for ulcers, creams and surgery
Bone marrow transplant
What is the sickle variant?
Substitution of glutamic acid -> valine at AA 6 of the mature beta-chain
Why has the sickle variant become common?
Carrier status confers resistance to malaria
What is the HbC variant?
Beta-chain variant, AA 6 Glu -> Lys
Hb crystallises and cells are rigid with mild haemolysis
Autosomal recessive
What is the HbE variant?
Beta chain, AA 26 Glu -> Lys
Abnormal Hb and decreased synthesis - thalassaemia
Autosomal recessive
What is HbKempsey?
Beta chain variant, AA 99 Asp -> Asn
Hb stays in high oxygen affinity state so less oxygen is released to the tissues
Autosomal dominant
What is thalassamia?
The most common group of single gene disorders.
Reduced synthesis of alpha or beta chains
What is the mechanism of disease in thalassaemia?
Reduced synthesis of alpha or beta chains -> excess globin chains precipitating and damaging the RBCs
Damaged cells broken down -> anaemia, iron loading, abnormal expansion of bone marrow -> skeletal changes (in beta-thal)
What is alpha thal?
Disorders of alpha chain synthesis
When does alpha-thal first have its effects?
In utero
Tetramers of γ4 and β4 can form in the absence of α chains: known as HbBart’s and HbH respectively – but neither release oxygen efficiently.
What is the common genetic basis for alpha-thal?
Deletions of alpha-Globin genes
Describe severe alpha-thal
Infants make only Hb Bart’s (γ4) – 4 genes are deleted. There is generalised fluid accumulation (hydrops fetalis) and hypoxia, which is usually fatal.
Describe HbH
Characterised by HbH (β4) – 3 genes are deleted.
Bone deformities, an enlarged spleen and fatigue. This is severe, but it can be treated.
Describe the alpha globin genes
2 copies of alpha globin gene per chromosome
Alpha2 gene produces ~2-3x more than Alpha1