Extra Hb Structure and function

Question 1

Explain how mutations in globin genes can cause functional abnormalities in haemoglobin

Answer 1

-Mutations can change the amino acid sequence and structure of the globin chains or the haem group, causing either an increased oxygen affinity, reduced oxygen affinity, increased tendency to oxidise or an unstable quaternary structure.
		//Histidine residues hold the haem in place

Question 2

What kinds of mutation in the globin genes cause high affinity haemoglobin?

Answer 2

• A mutation that interferes with the alpha1Beta2 bonds, affecting rotation and co-cooperativity
• A mutation that affects the carboxyterminal end of the protein, leading to hindered movement of the tetramer
• A mutation that interferes with 2-3-DPG binding
• Any of these can lead to high affinity haemoglobin
• e.g Hb Luton

Question 3

-What kinds of mutation in the globin gene cause a low affinity haemoglobin?

Answer 3

• A mutation affecting the alpha beta 2 contacts lead to the molecule favouring deoxy form, due to alteration of the angle of the haem group.
• Hb S is a low affinity haemoglobin
• Hb Kansas is another example

Question 4

-What kinds of mutation in the globin gene can cause methaemoglobinaemia?

Answer 4

• Methaemoglobinaemia is caused by haemoglobins that have an increased tendency to oxidise.
• This can be caused by a mutation that replaces a histidine residue in the haem group with a tyrosine.
• This leads to iron being stabilised in its ferric state, the haemoglobin is ‘frozen’ or ‘paralysed’.
• Hb M (e.g Hyde Park, a sub type) is an example of a haemoglobin that leads to methaemoglobinaemia

Question 5

What kinds of mutation in the globin gene can lead to unstable haemoglobins?

Answer 5

• A mutation can affect the secondary structure of haemoglobin and the alpha1beta1 contacts or the ‘haem pocket’. (Histidines that hold the haem together)
• When this structure is affected by a mutation, it can allow water to enter the haem pocket and cause oxidative damage.
• Oxidation leads to precipitation of haemoglobin (Heinz bodies) and damages the cell so it becomes more rigid.
• Hb Koln is an example of an unstable haemoglobin