Hemoglobinopathies

Question 1

Normal Hemoglobin contains a2b2 subunits. What would happen if it was a homotetramer?

Answer 1

Poor O2 carrier and Insoluble

Question 2

Describe the alpha cluster of hemoglobin genes. What chromosome is it on? Which genes are located there? When is each gene expressed?

Answer 2

Chromosome 15

Zeta-alpha-alpha

Zeta expressed in embryonic.
Alphas expressed fetal-adult

Question 3

Describe the betacluster of hemoglobin genes. What chromosome is it on? Which genes are located there? When is each gene expressed?

Answer 3

Chromosome 11

epsilon-gammaG-gammaA-delta-beta

Epsilon=embryonic
Gammas=Fetal
Delta and Beta=Adult

Question 4

What is the role of the Locus Control Region?

Answer 4

Control which of the globin gene promoters are active at any given time.

Question 5

What are the 3 classes of hemoglobin disorders?

Answer 5

1. Structural Variants (altered gobin properties)
2. Thalassemias (low levels of one globin)
3. Globin switching (persistence of fetal hemoglobin)

Question 6

What causes sickle cell disease?

Answer 6

A missense mutation in the Beta-globin gene (A:T sub causing Glu–> Val**).

These tend to form polymers and block of capillaries.

Heterozygotes have “sickle cell trait”

Question 7

What causes Hemoglobin C disease?

Answer 7

A missense mutation in the Beta-globin gene ( A:T sub causing Glu–> Lys**).

Question 8

A patient walks into your clinic and tells you he thinks he might have sickle cell anemia. After examining him, he shows all the classic signs. How can you confirm the diagnosis?

Answer 8

Use the restriction enzyme Mst II which cleaves normal Beta-globin gene sequence. If patient carries 1 or more sickle cell genes, you will see a larger band than expected.

(mountain standard time 2- they have a hard time carrying oxygen in the mtns)

Question 9

A patient walks into your clinic and tells you he thinks he might have sickle cell anemia. After examining him, he shows signs of a hemoglobin disorder but you cant tell him if it is Hemoglobin C or sickle cell. How can you confirm a diagnosis?

Answer 9

Gel electrophoresis:

Normal Hemoglobin is more NEGATIVE
Sickle=neutral
C=Positive

Question 10

Name conditions that lock hemoglobin in the relaxed and tense states.

Answer 10

Relaxed: polycythemia
Tense: cyanosis

Question 11

Alpha-thalassemias are associated with ___________, while beta-thals are associated with _________

Answer 11

deletions

mutations

Question 12

What are the 6 genotypes and associated pheotypes of Alpha thalassemia?

Answer 12

Because there are 2 alpha genes on each chromosome we have the following:
++/++ =Normal
++/+- =Silent carrier
++/– = Thal 1 (mild anemia) *plus on 1 chromosome only
+-/+- =Thal 2 (mild anemia)
+-/– = HbH disease: Severe anemia (beta tetramers)
–/– = fetal death (gama tetramer)

Question 13

What is the difference between a B-thalassemia minor and major “Cooley’s anemia”?

Answer 13

Majors have no completely functional genes
(may have B0 or B+, not B-wild type)

Minor- have at least one wildtype copy of B

Question 14

What is the difference between a simple and a complex thalassemia?

Answer 14

Simple-mutations that target only B-globin gene

Complex-Target other genes in B-cluster or Locus of Control Region (may cause HPFH)

Question 15

What are 2 causes of Hereditary Persistance of Fetal Hemoglobin?

Answer 15

1. Large Deletions bringing the enhancer closer to gamma globin gene
2. Promotor mutation that blocks inhibition

(beta and delta globin genes deleted)

Question 16

An father has a brother with sickle cell. What are the fathers chance of passing a copy of the affected allele to future children?

Answer 16

2/3 chance he is a carrier
1/2 chance he passes it on

1/3 his child will inherit the Hs allele

Question 17

Which population is MOST at risk for having a child with Hydrops fetalis?

Answer 17

Asias.
Africans usually have +-/+- Genotypes
Asians usually have ++/– genotypes.

Question 18

Why don’t children with B-thalassemia have symptoms for a few months?

Answer 18

Because of fetal hemoglobin switching.

Question 19

β0-thalassemia

Answer 19

Zero beta-globin synthesis. Caused by deletion of gene, nonsense mutation, frameshift mutation in early beta coding region. Generally this leads to death after birth.

Question 20

β+-thalassemia

Answer 20

Most common beta-thalassemia. Some beta hemoglobin still made. Often caused by mutations affecting transcription, protein stability, etc.

Question 21

What are the characteristics of Hemophilia A?

Answer 21

Spontaneous Bleeds, bruising, wound healing

F8 (factor VIII) mutation