Hemoglobinopathies Flashcards
The major form of adult hemoglobin
(HbA) is a α2β2 tetramer of two α- and two β-globin chains.
Each globin contains one __________, so one HbA can simultaneously bind ______ oxygen molecules.
heme group with a covalently linked iron that binds oxygen,
four oxygen molecules.
All of α and α-like genes are in the α-cluster on chromosome _____, while all of β and β-like genes are in the β-cluster on chromosome ____
16
11
___ copies of a in an alpha cluster
2
___ copies of B in a B-cluster
1
a-cluster
α-cluster: zeta-alpha2-alpha1
ζ-α2-α1
the genes in a cluster have the same
5’–3’ txn orientation
B-cluster
epsilon-gammaG-gammaA-delta-beta (ε-γG-γA-δ-β)
Pseudo gene
esembles a gene but makes no protein. ψζ, ψα, and ψβ are all pseudogenes.
The 5’-to-3’ spatial order of genes within each cluster coincides with the ______
temporal order of their expression during development.
The sequential expression of these genes during development is under the regulation of _____), which is located ________ of each cluster
of the Locus Control Region (LCR),
at the most upstream region of each cluster
t is currently thought that the distance between the LCR and a particular globin gene affects its _____
expression
The LCR makes physical contact with the _____ and/or _____ regulatory regions via specific transcriptional factors to influence gene expression.
promotor
negative
Deletions of the entire LCR of the beta cluster cause _____, a condition in which________ leads to precipitation of the ______
beta-thalassemias,
zero β-globin synthesis
the α-globin chains.
Adults have two Hb forms, which are made in the
bone marrow:
major form: HbA = α2β2 (97%)
minor form : HbA2 = α2δ2 (2%)
Note that δ level is much lower than β because δ has a weaker promoter.
Embryonic hemoglobins are made in the
yolk sac
Embryonic hemoglobin s
ζ2ε2 = Hb Gower I α2ε2 = Hb Gower II ζ2γ2 = Hb Portland
Fetal hemoglobins are made in
the liver
fetal hemoglobins
α2γ2 = HbF
Globin Switching
(i) turn-off of ζ and ε, turn-on of α and γ during early embryogenesis.
(ii) turn-offofγ,turn-on of β and δ around the time of birth.
Significance of Globin Switching
HbF has higher affinity for O2 at low pO2 than HbA. Thus, HbF in fetal blood is better suited to bind O2 at the placenta (lower pO2) than HbA, which binds O2 at the lung (higher pO2).
Genetic Variants of Hemoglobin
~ 600 variants of hemoglobin. About half of them are clinically significant.
Why do you need to study hemoglobinopathies?
hemoglobinopathies are among the best understood genetic disorders at molecular level. You can find almost any type of disease-causing mutations in hemoglobin disorders. Thus, they serve as great examples to illustrate the principal molecular mechanisms underlying human genetic disorders.
Structural Variants (qualitative hemoglobinopathies)
Mutations that alter the globin polypeptide properties without affecting its synthesis. Most structural variants are found in the β-globin chain. These mutations may alter O2 binding such as HbKemsey (too tight) and HbKansas (too weak), cause heme loss and denaturation of Hb, or make Hb less soluble such as HbS and HbC. Some can lead to serious red blood cell (RBC) diseases.
genetic variants of hemoglobin:
- structural varaints (qualatative)
- thalassemia (quantative)
- heriditary persistence of fetal hemoglobin (HPFH)
Thalassemias (quantitative hemoglobinopathies)
Disorders of imbalanced globin levels resulted from markedly reduced or no synthesis of one globin type. Can be caused by virtually all types of genetic mutations including deletions, missense and nonsense mutations, and defective transcriptional control.
Hereditary Persistence of Fetal Hemoglobin (HPFH)
HPFH is a group of clinically benign conditions that impair the perinatal switch from γ- to β-globin synthesis, leading to continued high-level production of HbF in adults.
Sickle cell anemia (HbSS)
Most common among people of African origin, where carrier frequency is ~10%.
Single base mutation at codon#6 in the β-globin gene changes glutamate to valine. HbS is 80% less soluble than HbA when not bound to O2, and polymerizes into long fibers that distort the RBC into a characteristic sickle shape. These sickled cells become lodged in the micro-capillaries and further exacerbate the sickling crisis.
Hemoglobin C disease (HbCC)
A milder form of hemolytic anemia than sickle cell anemia. Caused by a single base mutation at codon#6 of the β-globin gene, changing glutamate to lysine. HbC is less soluble than HbA and tends to form crystals, reducing the deformability of RBC.
HbS or HbC trait
Both sickle cell anemia and hemoglobin CC disease are of autosomal recessive inheritance. Sickle cell trait (HbS trait) or hemoglobin C trait (HbC trait) describes the conditions expressed in individuals who are heterozygous of HbS/HbA and HbC/HbA, respectively. They are clinically normal except when under severe low pO2 stress.
Hemoglobin SC disease
Compound
Compound heterozygotes (βS/βC) have a milder anemia than sickle cell disease.
HbS Diagnosis Using RFLP
A recognition site (CCTNAGG) of the restriction enzyme MstII is destroyed in exon 1 by the A-to-T change in the βS mutant allele. The normal allele βA gives 1.15 kb + 0.20 kb fragments, whereas the βS mutant allele give one1.35 kb fragment.
βA
-Pro-Glu-Glu- -CCTGAGGAG- MstII site present
βS
-Pro-Val-Glu- -CCTGTGGAG-
MstII site gone
βC
-Pro-Lys-Glu- -CCTAAGGAG- MstII site present
Thalassemias are caused by an imbalance in the relative levels of the________, which leads to the ______
α and β glob in chains
precipitation of the globin in excess and decreases the life span of the RBC.
MstII can distinguish between ______but not between _____
βA and βS
βA and βC.
A functional Hb tetramer is composed of
two α (or α-like) chains and two β (or β-like) chains. Homotetramers (e.g. α4, β4, γ4) are poor O2 carriers and precipitate inside the RBC.
α -Thalassemias are mostly caused by:
α -Thalassemias
