Hemoglobinopathies

Question 1

All of the alpha and alpha-like genes are in the alpha-cluster on which chromosome?

Answer 1

Chr 16

Question 2

All of the alpha and alpha-like genes are in the alpha-cluster on which chromosome?

Answer 2

Chr 16

Question 3

How many copies of alpha are there in the alpha-cluster?

Answer 3

Two copies

Question 4

How many copies of beta are in the beta-cluster?

Answer 4

One copy

Question 5

What is the order of the genes of the alpha-cluster?

Answer 5

zeta - alpha 2 - alpha 1

Question 6

What is the order of the genes of the beta-cluster?

Answer 6

epsilon - gamma G - gamma A - delta - beta

Question 7

How many copies of alpha are there in the alpha-cluster?

Answer 7

Two copies

Question 8

How many copies of beta are in the beta-cluster?

Answer 8

One copy

Question 9

What are the components of the minor type of adult hemoglobin and why is it only expressed at 2% of the total adult hemoglobin expression?

Answer 9

Minor form = HbA2 = 2 alphas + 2 deltas

Delta level is much lower because delta-cluster has a weaker promoter than beta-cluster

Question 10

What are the four forms of hemoglobin present during embryonic and fetal development?

Answer 10

HbF = 2 alphas + 2 gammas (made in the liver)

Hb Gower I = 2 zetas + 2 epsilons

Hb Gower II = 2 alphas + 2 epsilons

Hb Portland = 2 zetas + 2 gammas

Question 11

What is a pseudogene?

Answer 11

Resembles a gene but makes no protein

psi-alpha, psi-beta, and psi-zeta are all pseudogenes

Question 12

What type of globin switching occurs around the time of birth?

Answer 12

Turn OFF: gamma

Turn ON: beta and delta

Question 13

Where is the LCR (locus control region) located relative to the alpha and beta-clusters?

Answer 13

At the most upstream region of each cluster

Question 14

What are the components of the minor type of adult hemoglobin and why is it only expressed at 2% of the total adult hemoglobin expression?

Answer 14

Minor form = HbA2 = 2 alphas + 2 deltas

Delta level is much lower because delta-cluster has a weaker promoter than beta-cluster

Question 15

What are the four forms of hemoglobin present during embryonic and fetal development?

Answer 15

HbF = 2 alphas + 2 gammas (made in the liver)

Hb Gower I = 2 zetas + 2 epsilons

Hb Gower II = 2 alphas + 2 epsilons

Hb Portland = 2 zetas + 2 gammas

Question 16

Thalassemias are examples of what type of hemoglobinopathy?

Answer 16

Quantitative hemoglobinopathies

because they’re the result of imbalanced globin levels from reduced or no synthesis of one globin type.

Question 17

What mutation is seen in sickle cell anemia?

Answer 17

Single base mutation at codon 6 in the beta-globin gene –> changes Glutamate to Valine

Question 18

What are RBCs distorted into the characteristic sickle shape with SCA?

Answer 18

because HbS is 80% less soluble than HbA (without O2) so it polymerizes into long fibers => distorted RBC

Question 19

Structural variants are examples of what type of hemoglobinopathy?

Answer 19

Qualitative hemoglobinopathies

because they alter the globin polypeptide properties without affecting synthesis.

Question 20

How can the MstII restriction enzyme be used to diagnose the presence of HbS mutant allele?

Answer 20

A normal allele will yield a 1.15kb fragment and a HbS allele will yield a 1.35kb fragment

The restriction site is present with normal allele and HbC allele but not with HbS allele.

MstII restriction site: CCTNAGG

Question 21

A homozygous state of alpha-thal-1 (–/–) lead to what?

Answer 21

hydrops fetalis

Question 22

What mutation is seen in sickle cell anemia?

Answer 22

Single base mutation at codon 6 in the beta-globin gene –> changes Glutamine to Valine

Question 23

What are RBCs distorted into the characteristic sickle shape with SCA?

Answer 23

because HbS is 80% less soluble than HbA (without O2) so it polymerizes into long fibers => distorted RBC

Question 24

What differences are seen in Hemoglobin C disease compared to SCA?

Answer 24

Glutamate changes to Lysine (instead of valine)

HbC forms crystals (instead of long fibers)

Question 25

How can the MstII restriction enzyme be used to diagnose the presence of HbS mutant allele?

Answer 25

A normal allele will yield a 1.15kb fragment and a HbS allele will yield a 1.35kb fragment

The restriction site is present with normal allele and HbC allele but not with HbS allele.

MstII restriction site: CCTNAGG

Question 26

A homozygous state of alpha-thal-1 (–/–) lead to what?

Answer 26

hydrops fetalis

Question 27

Depending on the range of the deletion, people with deletions that remove the delta and beta genes, while preserving gamma, can have what sorts of thalassemia?

Answer 27

delta-beta-zero-thalassemia
or
HPFH

Question 28

beta-Thalassemia minor is characterized by what clinical presentations?

Answer 28

None. Clinically normal (carriers of one beta-thal allele)

Question 29

Mutations or deletions that impair the production of the beta-globin chain alone results in what type of beta-thal?

Answer 29

Simple beta-thal

Question 30

Complex thalassemia is caused by what?

Answer 30

Large deletions that remove the beta-globin gene plus other genes in the beta-cluster

Question 31

What is the most common form of beta-thalassemia?

Answer 31

Beta-plus-thalassemia = 90% of cases

some beta-globin is made so some HbA is present

Question 32

Depending on the range of the deletion, people with deletions that remove the delta and beta genes, while preserving gamma, can have what sorts of thalassemia?

Answer 32

delta-beta-zero-thalassemia
or
HPFH

Question 33

Increased gamma-globin expression in HPFH (hereditary persistent fetal hemoglobin) can be caused by what two mechanisms?

Answer 33

(1) extended deletion of additional downstream sequences (brings cis-acting enchanter closer to gamma-globin gene)

or

(2) mutations in promoter region in a gamma-globin gene that destroys binding site of a repressor (relieving postnatal repression of gamma)