Molecular Genetics of Hemoglobinopathies

Question 1

What is the major hemoglobin form/structure, and what are its subunits?

Answer 1

HbA (adult hemoglobin), alpha2beta2

Question 2

What genes are found in the alpha cluster?

Answer 2

zeta-alpha2-alpha1

Question 3

What chromosome is the alpha cluster on? Beta?

Answer 3

alpha: ch 16
beta: ch 11

Question 4

how many copies of alpha genes are in the alpha cluster? Beta?

Answer 4

alpha: 2 copies
beta: 1 copy

Question 5

What genes are found in the beta cluster?

Answer 5

epsilon-gammaG-gammaA-delta-beta

Question 6

Is the LCR located upstream/downstream of the 2 clusters?

Answer 6

Upstream

Question 7

Deletion of _______ causes beta-thalassemia. Result?

Answer 7

LCR of beta cluster ==> no beta globin –> ppt of alpha globin

Question 8

How many alpha genes do we have?

Answer 8

4 (2 alleles with 2 alphas)

Question 9

Hb gower 1 subunits (embryonic)

Answer 9

zeta2-epsilon2

Question 10

Hb gower 2 subunits (embryonic)

Answer 10

alpha2-epsilon2

Question 11

Hb portland subunits (embryonic)

Answer 11

zeta2-gamma2

Question 12

HbF subunits (fetal)

Answer 12

alpha2-gamma2

Question 13

HbA2

Answer 13

alpha2-delta2 (<3.5%)

Question 14

How many Hb forms do adults have? Adult Hb made where?

Answer 14

2 - HbA and HbA2

made in bone marrow

Question 15

How many Hb forms do fetus have? Fetal Hb made where?

Answer 15

1 - alpha2gamma2

made in liver

Question 16

How many Hb forms do embryos have? Made where?

Answer 16

3 - 
     - Hb gower I: zeta2-epsilon2
     - Hb Gower II: alpha2-epsilon2
     - Hb portland: zeta2-gamma2
made in yolk sac

Question 17

In globin switching, what genes get turned off and what genes get turned on at embryogenesis? At what location?

Answer 17

Turn off: zeta and epsilon
turn on: alpha and gamma
at alpha locus

(embryo–> fetus)

Question 18

In globin switching, what genes get turned off and what genes get turned on at birth? At what location?

Answer 18

Turn off: gamma
Turn on: beta and delta
at beta locus

(fetal –> adult)

Question 19

How much less soluble is HbS than HbA?

Answer 19

80%

Question 20

What inheritance pattern is Sickle Cell Anemia?

Answer 20

Autosomal recessive

Question 21

What is the mutation in Hemoglobin C (HbCC)?

Answer 21

point mutation: Glu6Lys / E6K in beta globin gene

Question 22

What inheritance pattern is Hemoglobin C disease?

Answer 22

autosomal recessive

Question 23

What chaos does HbCC invoke in the cell?

Answer 23

HbC (like HbS) is also less soluble than HbA

it forms crystals and cause lysis of RBC

Question 24

What is a common diagnosis method for Sickle cell disease?

Answer 24

HbS diagnostic using MstII restriction enzyme in RFLP

• normal beta globin allele gives 2 fragments
• mutant beta globin allele gives 1 long fragment

Question 25

Phenotype and geographical distribution of:

αα/α-

Answer 25

silent carrier

africa, mediterranean, asia

Question 26

Phenotype and geographical distribution of:

αα/–

Answer 26

mild anemia: alpha-thalassemia I

```
Southeast Asia (–
knock out both copies on 1 chromosome)
~~~

Question 27

Phenotype and geographical distribution of:

α-/α-

Answer 27

mild anemia: alpha-thalassemia II
africa, mediterranean, asia

(knock out 1 copy on each chromosome)

Question 28

Phenotype and geographical distribution of:

α-/–

Answer 28

Severe anemia

Southeast Asia(–)

Question 29

Phenotype and geographical distribution of:

–/–

Answer 29

Hydrops fetalis

Southeast Asia(–)

Question 30

Thalassemia major

• whats wrong with the genes?
• phenotype?

Answer 30

2 absent beta globin genes or severely abnormal gene

-severe anemia

Question 31

Thalassemia Minor

• whats wrong with the genes?
• phenotype?

Answer 31

1 normal gene, 1 abnormal beta globin gene

Question 32

What mode of inheritance is Thalassemia?

Answer 32

autosomal recessive

Question 33

Beta^o thalassemia has too much/too little beta globin synthesis?

Answer 33

too little - 0 beta globin synthesis

due to del, nonsense, fs,

Question 34

Beta^ + thalassemia has none/some beta globin made

Answer 34

some

due to mut affecting txn, RNA processing, prot stability

Question 35

Alpha-thalassemia defect occurs when? (think development)

Answer 35

fetal and postnatal defect in alpha globin gene

Question 36

Beta-thalassemia defect occurs when? (think development)

Answer 36

post natal defect only (globin switch) in beta blobin gene or LCR/beta gene cluster

Question 37

Hereditary persistence of fetal Hb (HPFH) cause? effect?

Answer 37

deletion in delta and beta genes –> no delta or beta synthesis

results in increased gamma globin expression

Question 38

What subunits are present in HPFH? Phenotype?

Answer 38

alpha2gamma2 , disease free! No phenotype!