Genetic basis of Hemoglobinopathies, Thalassemia and Hemoglobin

Question 0

Thalassemia

Answer 0

Quantitative changes: decreased or absent globin chain synthesis

Question 1

Hemoglobinopathies

Answer 1

Qualitative change: mutation in nucleotide sequence of globin chain

Question 2

Hemoglobin S

Answer 2

-Single nucleotide transversion mutation (GAG->GTG): Beta globin gene Glutamic acid to Valine at position 6
-HbS therefore moves slower in electrophoresis
-homozygous inheritance (Hbss) causes Sickle cell anemia
Treatment: increase HbF by demethylation of suppression promoters and increasing expression of fetal globins (gamma).
Drug based interventions alter epigenetic gene regulatory mechanisms and may change acetylation of chromatin proteins->altering gene silencing->increasing HbF
Treat with: Hydroxyurea, 5-azacytidine (decatibine; demethylating agent), Butyrate compounds (inhibit histone deacetylation).

Question 3

Hemoglobin C (HbC)

Answer 3

Glu->Lys
positively charged lysine so moves the slowest in electrophoresis gel.
-lower solubility than HbA so crystallizes in RBCs
-Patients having HbSC, may have episodes of sickling similar to sickle cell anemia

Question 4

Thalassemia: alpha and beta

Thalassa (sea) Haima (blood)

Answer 4

Syndromes in which the rate of sythesis of a globin chain is reduced.
alpha thalassemia: reduced alpha chain synthesis
-common in asia, africa, meditteraneans
-due to unequal crossing over during homologous recombination
-common cause is gene deletion
-most severe form is Hemoglobin Bart Hydrops fetalis-all 4 alphas deleted (aggregation of gamma tetramers).
-mild form: Hemoglobin HBH. 1/3 of affected individuals. compatible with life. deletion or dysfunction of 3 or 4 alphas (forms Beta 4 tetramers)
beta thalassemia: reduced beta chain synthesis

Question 5

Hemophilia A

Answer 5

On long arm of X-chromosome

• Large intron INversion (40% of cases) that disrupts FVIII gene. deletions, insertions, and point mutations account for remaining 50-60% of hemophilia A mutations (allelic heterogeneity)
• misalignment during homologous recombination.exons 1-22 are displaced towards the telomere and are oriented in a direction opposite to their normal orientation.

Question 6

Beta Thalassemia

Answer 6

AR-higher carrier frequency in the Mediterranean, North Africa and the middle east.
-many mutations that cause Beta thalassemia (allelic heterogeneity)
many types:
-B+ thalassemia: reduced gene expression
-Bo thalassemia: complete suppression of gene expression
Net effect: absent or reduced synthesis of Beta globin chains of hemoglobin
-excessive Alpha globin (do not form tetramers but bind RBC membranes) chains ppt. and result in hemolytic anemia.
-Bone marrow tries to compensate and expands to perform erythropoiesis (extramedullary erythropoiesis) and leads to bone deformity and fractures.

Question 7

3 Main forms of beta thalassemia are:

Answer 7

Beta thalassemia major (‘Cooley’s Anemia’ and Mediterranean Anemia’):
-Subjects are homozygotes or compound heterozygotes for Bo or B+ genes-two severe mutations
-very low or absent HbA levels, high HbA2 and HbF levels
Beta thalassemia Intermedia:
-mostly homozygotes or compound heterozygotes (different B+ mutations on the B-globin genes)-one severe mutation second mutation is less severe
-low HbA levels-as there is some Beta globin synthesis
Beta- thalassemia minor (“carrier”, ‘trait’,’heterozygous’)
-almost normal HbA levels