52: Hemoglobinopathies

Question 1

Where are the α-like and β-like

globin genes clustered?

Answer 1

Chromosomes 11 and 16

Question 2

How many α-globin genes are on Chromosome 16?

Answer 2

2 α-globin genes

4 total α-globin genes in a normal individual

Question 3

How many β-globin genes are on Chromosome 11?

Answer 3

1 β-globin gene

2 β-globin genes in a normal individual

Question 4

HbA

Adult

Answer 4

90-95%

α2β2

Question 5

HbF

Fetal

Answer 5

1-2%

α2γ2

Question 6

HbA2

Answer 6

3-5%

α2δ2

Question 7

Embryonic hemoglobins

Answer 7

have zeta and epsilion chains.

Question 8

Hemoglobinopathies

Answer 8

family of genetic disorders caused by production of a structurally abnormal hemoglobin or by synthesis of insufficient amounts of
normal hemoglobin

Question 9

Hemoglobinopathies Qualitatitive change:

Answer 9

Mutation in nucleotide sequence of globin chain

Question 10

Thalassemia Quantitative change:

Answer 10

Decreased or absent globin chain synthesis

Question 11

Hemoglobin S

Answer 11

point mutation in β-globin at 6th position

Glutamate –> Valine (GAG>GTG; missense)

HbS slower to anode than HbA

Homozygous (HbSS): Sickle Cell

Question 12

Sickle Cell

Answer 12

Autosomal Recessive

Sickle Cell crisis

occlusion of vessels

anemia, hemolysis, and vaso-occulsive ischemia

Question 13

HbS Treatment

Answer 13

Hydroxyurea:

inhibit histone deacetylation leading to more HbF formation

reduced sickling b/c inhibition of HbS polymerization

Question 14

HbAS

Answer 14

sickle cell heterozygous carrier

produce normal and abnormal hemoglobin

can develop sickle crisis in low oxygen saturation

Question 15

Survival Advantage

Answer 15

People who inherited one sickle hemoglobin gene (heterozygotes) to combat malaria

Question 16

Hemoglobin C

Answer 16

point mutation in β-globin at 6th position

Glutamate –> Lysine

moves slowest to anode

mild hemolysis

low solubility, crystallizes in RBC

Question 17

HbSC

Answer 17

two different mutations of β-globin gene

S and C mutation

mild sickling episodes

Question 18

Hemoglobin Electrophoresis

Answer 18

HbC (- end)
HbS
HbF
HbA(+end)

Question 19

RFLP

Answer 19

mutant genes will have larger fragments

Question 20

Thalassemias

Answer 20

rate of synthesis of a globin chain is reduced

imbalance alpha/beta chain ratio

Question 21

a-Thalassemia

Answer 21

reduced alpha chain synthesis

Question 22

Cause of a-Thalassemia?

Answer 22

a-globin gene deletion can be caused by unequal crossing over during homologous recombination

Question 23

Hemoglobin Bart hydrops fetalis (Hb Bart) Syndrome

Answer 23

most severe form of a-Thalassemia

cis x cis parents

aggregation of 4 tetramers: γ4 tetramers

All four α-globin alleles are deleted (inactivated) and no HbF or HbA

neonatal death

Question 24

Hemoglobin H (HbH) Diseases

Answer 24

deletion of three of the four α-globin alleles

trans x cis parents

infancy or childhood

mild-to-moderate anemia or hepatospenomegaly

bone changes

compatible with survival into adulthood

aggregation of β4 tetramers

Question 25

α-thalassemia carrier/trait

Answer 25

deletion or inactivation of two
α-globin genes (cis or trans)

normal or slightly low hemoglobin levels

Question 26

β-thalassemia

Answer 26

Autosomal recessive

Allelic heterogeneity

β+ mutation: reduced gene expression

β0 mutation: complete suppression of gene expression

absent or reduced of synthesis of the β-globin chains

Excessive a-globin result in severe
hemolytic anemia

Bone marrow tried to produce more RBC but leads to bone deformity and fractures

Question 27

β-thalassemia major

Answer 27

“Cooley’s Anemia’ and ‘Mediterranean
Anemia”

homozygotes or compound heterozygotes for β0 or β+ genes (two severe mutations)

mutations in both β- globin genes

Very low or absent HbA levels

High HbA2 and HbF levels

Question 28

β-thalassemia intermedia

Answer 28

homozygotes or compound heterozygotes

(different β+ mutations
on the β-globin genes)

one severe mutation, second mutation is less
severe or two less severe mutations

Low HbA levels

High HbA2 and HbF levels

Question 29

β-thalassemia minor

Answer 29

“β-thalassemia carrier, β-thalassemia trait, or heterozygous β-thalassemia”

one normal, one mutant β-globin gene

Almost normal HbA levels

Question 30

Carrier screening

Answer 30

introduced in several Mediterranean populations to reduce number of newborns with thalassemia

Question 31

Molecular basis of β-thalassemia

Answer 31

mutations in HBB gene on Chromosome 11

excess a-chains, bind to membrane and produce damage , toxic at high concs. –> hemolysis

Allelic heterogeneity- 150 different mutations

Question 32

β-thalassemia Treatment

Answer 32

bone marrow

transplantation from an HLA-identical sibling

Question 33

Hemophilia A & B

Answer 33

X-linked recessive bleeding disorders

deficiency in Factor 8 (Hem A) and Factor 9 (Hem B)

hemorrhage into joints and muscles

easy bruising and prolonged bleedings

Question 34

Genetics of Hemophilia A & B

Answer 34

Genes for both Factors on long arm of X-chromosome

Factor 8 (large): 40% large inversion disrupting gene or 60% deletions/insertions/point mutation

Factor 9 (small): point mutations and deletions in gene

Question 35

Inheritance Pattern for Hemophilia

Answer 35

Affected male → carrier female → Affected male

Carrier mother, 50% change passing faulty X to daughter

Affected father will always pass affected gene to daughters (obligate carriers)

Question 36

Phenotypes of carrier females

Answer 36

generally asymptomatic b/c of random X inactivation/ Lyonization - normal hemostasis

Manifesting heterozygote: lower level of clotting
factors b/c of skewed X
inactivation

Question 37

Recombinant protein

Answer 37

manufacture of clotting factors replaces pooled serum