Hemoglobinpathies

Question 1

Mutations have been found to cause disease through one of four different effects on protein function. They are:

Answer 1

1. loss of function
2. gain of function
3. heterochronic expression
4. ectopic expression

Question 2

Gain of function mutation:

Answer 2

the acquisition of a novel property by the mutant protein

Question 3

Heterochronic expression mutation:

Answer 3

the expression of a gene at the wrong time

Question 4

Ectopic expression:

Answer 4

the expression of a gene in the wrong place

Question 5

alpha-thalessemias are due to what type of mutation?

Answer 5

• loss of function due to deletion
  
  • leads to a reduction in gene dosage

Question 6

The severity of a disease that results from loss-of-function mutations can generally be correlated to the:

Answer 6

• amount of function lost
• retention of a small degree of residual function by the mutant protein greatly reduces the severity of the disease

Question 7

hemoglobin Kempsey

Answer 7

locks hemoglobin in its high oxygen affinity state, thereby reducing oxygen delivery to tissues.

Question 8

Beta-thalassemias are characterized by:

Answer 8

• a reduction in the abundance of beta-globin
• due to loss of function mutation

Question 9

Sickle Cell Disease:

Answer 9

• due to an amino acid substitution that has no effect on the ability of sickle hemoglobin to transport oxygen.
• Rather, unlike normal hemoglobin, sickle hemoglobin chains aggregate when they are deoxygenated to form polymeric fibers that deform red blood cells.

Question 10

Heterochronic and ectopic mutations

Answer 10

• alter the regulatory regions of a gene to cause its inappropriate expression, at an abnormal time or place.

Question 11

Hereditary Persistence of Fetal Hemoglobin (HPFH):

Answer 11

• mutations in hemoglobin regulatory elements lead to the continued expression in the adult of the gamma-globin gene, which is normally expressed at high levels only in fetal life.

Question 12

Globin switching:

Answer 12

• the change in the expression during development of the various globin genes

Question 13

The hereditary disorders of hemoglobin can be divided into three broad groups. They are:

Answer 13

1. Structural variants
2. Thalessemias
3. Hereditary persistence of fetal hemoglobin (HPFH)

Question 14

Structural variants:

Answer 14

alter the globin polypeptide without affecting its rate of synthesis

Question 15

Thalessemias:

Answer 15

• decreased synthesis (or, rarely, extreme instability) of one or more of the globin chains
• results in an imbalance in the relative amounts of the alpha and beta chains

Question 16

Hereditary persistence of fetal hemoglobin (HPFH):

Answer 16

• impair the perinatal switch from gamma-globin to beta-globin synthesis

Question 17

The hemoglobin structural variants can be separated into three classes. They are:

Answer 17

1. hemolytic anemia
2. altered oxygen transport
3. thalessemias

Question 18

Cinical features of Sickle Cell Disease:

Answer 18

• a tendency of the red blood cells to become grossly abnormal in shape (i.e., to sickle) under conditions of low oxygen tension
• hemolytic condition

Question 19

Molecular pathology of Sickle Cell Disease (HbS):

Answer 19

• single change in the beta-globin gene
  
  • (glu-6 to val)

Question 20

Sickle Cell Anemia: how sickling occurs and its consequences.

Answer 20

• in deoxygenated blood, HbS is only 1/5 as soluble as normal hemoglobin
  
  • mutation makes surface hydrophobic
• HbS aggregate in the form of rod-shaped polymers or fibers, which distort the erythrocyte to a sickle shape.
• mis-shapen erythrocytes are less deformable
  
  • cannot squeeze in single file through capillaries, thereby blocking blood flow and causing local ischemia.

Question 21

HbC is due to:

Answer 21

• a substitution at the 6th position of the beta-chain
  
  • glu replaced by lys
  • mutation at same position as HbS

Question 22

Clinical features of HbC:

Answer 22

• less soluble than Hb A
• tends to crystallize in red blood cells, reducing their deformability in capillaries and causing a mild hemolytic disorder

Question 23

beta-0 thalassemia

Answer 23

no HbA is present

Question 24

beta+ thalassemia

Answer 24

some HbA present