52: Hemoglobinopathies Flashcards
Where are the α-like and β-like
globin genes clustered?
Chromosomes 11 and 16
How many α-globin genes are on Chromosome 16?
2 α-globin genes
4 total α-globin genes in a normal individual
How many β-globin genes are on Chromosome 11?
1 β-globin gene
2 β-globin genes in a normal individual
HbA
Adult
90-95%
α2β2
HbF
Fetal
1-2%
α2γ2
HbA2
3-5%
α2δ2
Embryonic hemoglobins
have zeta and epsilion chains.
Hemoglobinopathies
family of genetic disorders caused by production of a structurally abnormal hemoglobin or by synthesis of insufficient amounts of
normal hemoglobin
Hemoglobinopathies Qualitatitive change:
Mutation in nucleotide sequence of globin chain
Thalassemia Quantitative change:
Decreased or absent globin chain synthesis
Hemoglobin S
point mutation in β-globin at 6th position
Glutamate –> Valine (GAG>GTG; missense)
HbS slower to anode than HbA
Homozygous (HbSS): Sickle Cell
Sickle Cell
Autosomal Recessive
Sickle Cell crisis
occlusion of vessels
anemia, hemolysis, and vaso-occulsive ischemia
HbS Treatment
Hydroxyurea:
inhibit histone deacetylation leading to more HbF formation
reduced sickling b/c inhibition of HbS polymerization
HbAS
sickle cell heterozygous carrier
produce normal and abnormal hemoglobin
can develop sickle crisis in low oxygen saturation
Survival Advantage
People who inherited one sickle hemoglobin gene (heterozygotes) to combat malaria
Hemoglobin C
point mutation in β-globin at 6th position
Glutamate –> Lysine
moves slowest to anode
mild hemolysis
low solubility, crystallizes in RBC
HbSC
two different mutations of β-globin gene
S and C mutation
mild sickling episodes
Hemoglobin Electrophoresis
HbC (- end)
HbS
HbF
HbA(+end)
RFLP
mutant genes will have larger fragments
Thalassemias
rate of synthesis of a globin chain is reduced
imbalance alpha/beta chain ratio
a-Thalassemia
reduced alpha chain synthesis
Cause of a-Thalassemia?
a-globin gene deletion can be caused by unequal crossing over during homologous recombination
Hemoglobin Bart hydrops fetalis (Hb Bart) Syndrome
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
Hemoglobin H (HbH) Diseases
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
α-thalassemia carrier/trait
deletion or inactivation of two
α-globin genes (cis or trans)
normal or slightly low hemoglobin levels
β-thalassemia
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
β-thalassemia major
“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
β-thalassemia intermedia
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
β-thalassemia minor
“β-thalassemia carrier, β-thalassemia trait, or heterozygous β-thalassemia”
one normal, one mutant β-globin gene
Almost normal HbA levels
Carrier screening
introduced in several Mediterranean populations to reduce number of newborns with thalassemia
Molecular basis of β-thalassemia
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
β-thalassemia Treatment
bone marrow
transplantation from an HLA-identical sibling
Hemophilia A & B
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
Genetics of Hemophilia A & B
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
Inheritance Pattern for Hemophilia
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)
Phenotypes of carrier females
generally asymptomatic b/c of random X inactivation/ Lyonization - normal hemostasis
Manifesting heterozygote: lower level of clotting
factors b/c of skewed X
inactivation
Recombinant protein
manufacture of clotting factors replaces pooled serum
