Hemoglobin Variants

Question 1

What are the symptoms associated with sickle cell anemia & what is the biological cause of these symptoms?

Answer 1

• painful swelling of extremities & higher risk of stroke or bacterial infection
  
  • fibrous aggregates
    
    • clog small cappillaries & impede blood flow
  • more adherent to blood vessel walls
• anemia
  
  • sickled cells do not remain in circulation as long as normal RBC

Question 2

What is the mutation associated with sickle-cell anemia?

Answer 2

Glutamate to Valine in position 6 on the beta chain of hemogloin

Question 3

What is the shorthand for mutated hemoglobin Beta-chain in sickle-cell anemia?

Answer 3

HbS

Question 4

Does the HbS mutation affect oxygenated Hb or deoxygenated Hb?

Why?

Answer 4

deoxygenated

the new valine 6 lies on the surface of the T-state molecule

this new hydrophobic patch iteracts with a different hydrophobic patch (Phe 85 & Leu 88 of neighboring B-chain molecule) to initiate the aggregation process

In the R-state, the Phe 85 & Leu 88 are largely inside the protein, so they cannot interact with the Valine 6

Question 5

Sickle-cell anemia most commonly affects what demographic?

Why?

Answer 5

West Africans (1/100)

Heterogeneous individuals (1 HbS & 1 HbB) show an enhanced resistance to malaria

historically endemic regions have favored individuals with sickle-cell trait

Question 6

What is Thalasemia & what is the biological result of this condition?

Answer 6

loss or substantial reduction of a single hemoglobin chain

low levels functional hemoglobin & decreased production of RBC

anemia, fatigue, pale skin, & splee and liver malfunction

Question 7

How does alpha-thalassemia effect hemoglobin function?

Answer 7

alpha chain is not produced in sufficient quantity

hemoglobin tetramers are only beta chain - HbH

bind oxygen with high affinity & no cooperativity, – poor oxygen release at tissues

Question 8

How does beta-thalassemia effect hemoglobin?

Answer 8

beta chain is not produced in sufficient quantity

alpha chains form insoluble aggregates that precipitate inside immature red blood cells – leads to anemia

Question 9

What is the most severe form of beta-thalassemia?

Answer 9

thalassemia major or Cooley anemia

Question 10

Why are alpha-thalassemias more rare than beta-thalassemia?

Answer 10

• usually have 4 alleles of alpha-chain
  
  • so, the complete loss of alpha-chain requires disruption of 4 alleles
• only have 2 alleles of beta chain

Question 11

What chromosome contains the genes for the alpha chain?

The beta chain?

Answer 11

• alpha
  
  • the 2 genes are located next to each other on one end of chromosome 16
• beta
  
  • chromosome 11

Question 12

Why does the excess alpha chain not precipitate?

Answer 12

alpha-hemoglobin stabilizing protein (AHSP)

forms soluble complex wth newly synthesized alpha-chain monomers

Question 13

Where does the AHSP bind to the alpha-chain?

Answer 13

same face that beta-hemoglobin binds

Question 14

How does the Hb tetramer form if the newly synthesized alpha chain is bound to AHSP?

Answer 14

as beta-chain is expressed, it displacaes AHSP because the alpha-beta-dimer is more stable than the alpha-AHSP complex

Question 15

How is fetal hemoglobin different from adult hemoglobin?

Answer 15

it contains the gamma-chain in place of the beta-chain

Question 16

What is the name of the globin variant that is primarily expressed in the brain & retina? What is its function?

Answer 16

Neuroglobin

protecting neural tissues from hypoxia

Question 17

What is cytoglobin?

Answer 17

a monomeric globin protein widely expressed throughout the body

Question 18

Describe the specifics of oxygen binding for neuroglobin & cytoglobin.

Answer 18

IN teh deoxy state, both the proximal & distal histidines are coordinated to the iron atom

oxygen binding displaces the distal histidiene