Globin Genes

Question 1

% of world population who are carriers for haemoglobin disorders?

Answer 1

5%

Question 2

What is the general structure of haemoglobin?

Answer 2

Tetrameric protein: 2 alpha-like + 2 beta-like chains. 4 haem groups, each with an iron atom

Question 3

How many molecules of oxygen can 1 Hb carry?

Answer 3

4 (1 for each haem group)

Question 4

What are the embryonic haemoglobins?

Answer 4

Hb Gower 1 ζ2ε2, Hb Gower α2ε2, Hb Portland ζ2γ2

Question 5

What is the foetal haemoglobin?

Answer 5

HbF α2γ2

Question 6

What are the adult haemoglobins?

Answer 6

HbA α2β2, HbA2 α2δ2

Question 7

Which Globin is the most important from foetus to adult?

Answer 7

Alpha globin as it is present in all haemoglobins

Question 8

How are Globin genes arranged?

Answer 8

In clusters on chromosome 16, 11 (see if there are more)

Question 9

Are all globin genes functional?

Answer 9

No, some are non-functional and are remnants of evolution

Question 10

How many alpha and beta Globin genes are there in the diploid genome?

Answer 10

4 alpha

2 beta

Question 11

What % of chains are affected in 1 beta-gene variant & 1 alpha-gene variant respectively?

Answer 11

50% beta

~25% alpha

Question 12

S+S of sickle cell disease?

Answer 12

Abnormally shaped (sickled) RBCs, fingers of unequal and abnormal length, bony infarctions of phalanges and metacarpals
MI, stroke, ulcers, heart failure

Question 13

How does sickle cell disease lead to stroke?

Answer 13

Deoxygenated HbS forms roads and deforms cells -> sickled cells block capillaries (can’t squeeze through) -> MI

Question 14

What is the treatment for sickle cell disease?

Answer 14

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

Question 15

What is the sickle variant?

Answer 15

Substitution of glutamic acid -> valine at AA 6 of the mature beta-chain

Question 16

Why has the sickle variant become common?

Answer 16

Carrier status confers resistance to malaria

Question 17

What is the HbC variant?

Answer 17

Beta-chain variant, AA 6 Glu -> Lys
Hb crystallises and cells are rigid with mild haemolysis
Autosomal recessive

Question 18

What is the HbE variant?

Answer 18

Beta chain, AA 26 Glu -> Lys
Abnormal Hb and decreased synthesis - thalassaemia
Autosomal recessive

Question 19

What is HbKempsey?

Answer 19

Beta chain variant, AA 99 Asp -> Asn
Hb stays in high oxygen affinity state so less oxygen is released to the tissues
Autosomal dominant

Question 20

What is thalassamia?

Answer 20

The most common group of single gene disorders.

Reduced synthesis of alpha or beta chains

Question 21

What is the mechanism of disease in thalassaemia?

Answer 21

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)

Question 22

What is alpha thal?

Answer 22

Disorders of alpha chain synthesis

Question 23

When does alpha-thal first have its effects?

Answer 23

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.

Question 24

What is the common genetic basis for alpha-thal?

Answer 24

Deletions of alpha-Globin genes

Question 25

Describe severe alpha-thal

Answer 25

Infants make only Hb Bart’s (γ4) – 4 genes are deleted. There is generalised fluid accumulation (hydrops fetalis) and hypoxia, which is usually fatal.

Question 26

Describe HbH

Answer 26

Characterised by HbH (β4) – 3 genes are deleted.

Bone deformities, an enlarged spleen and fatigue. This is severe, but it can be treated.

Question 27

Describe the alpha globin genes

Answer 27

2 copies of alpha globin gene per chromosome

Alpha2 gene produces ~2-3x more than Alpha1