Term
|
Definition
hemoprotein (globin + prosthetic group)
quarternary structure
-prosthetic group of each subunit = HEME
-4 polypeptide chains, 4 molecules of heme, 4 ferrous (Fe2+) ions |
|
|
Term
|
Definition
2 csomes #11 each have one beta gene
2 csomes #16 each have 2 alpha genes
Hb has 2 alpha, 2 beta subunits
each alpha globin gene has about 1/2 the pr of one beta (so production of protein subunits is kept equal)
Thalassemia occurs when a globin gene fails, and production of globin protein subunits is thrown out of balance. Most types involve deletions or mutations which affect mRNA processing or translation, affect rate of synth of a particular alpha- or beta-globin chain.
the globin gene sequences are interrupted by 2 intron sequences, therefore exons are divided into 3 segments. |
|
|
Term
HbS - sickle cell anemia
What % of A-A are homo or heterozygous?
Symptoms?
Electrophoresis
Polymerization & transit time
Possible treatment? |
|
Definition
Result of a *single point mutation*
Glu->Val at position 6 causes h-phobic loop at N-term region of beta chain, exposed only when Hb is in deoxy form-> polymerization->distorted RBC
autosomal recessive (both parents have to have it)
As HbS in capillaries gives up its O2 to tissues, capillaries clog, blood flow slows down
Cells are rapidly sequestered, destroyed by spleen
Half-life of RBC --> 3-11 days
0.2% of US blacks are homozygous
7-9% of blacks are heterozygous
malaria-resistant (short half-life)
Vaso-occlusive crisis, pain in arms and legs, dactylitis, splenomegaly; pneumoccal infxns; CV problems; fatal by age 20 in 50% of those affected
HbS being less negative than HbA moves slower toward the anode
Delay time is shorter than capillary transit time, and polymerization and cellular deformation occurs while cell is in capillary, possibility of occluding the cell
Stem cell replacement
Gene therapy
*Hydroxyurea* - stimulate HbF production and delay time of Hb polymerization and transit of red cells through capillary microcirculation |
|
|
Term
What will a carrier for sickle cell have? (having the trait)
Full-blow disease? |
|
Definition
25% normal HbA
50% HbS
25% HbSS
Both copies of Hb beta gene have an S mutation (all beta subunits are replaced by Beta S) |
|
|
Term
Hemoglobin C
Double heterozygous with HbS |
|
Definition
One of the beta subunits is replaced by Beta C, one is replaced with Beta S
Will have sickle cell HbC
Glu->Lys at position 6 of beta globin chain
rarer, milder than HbS
doubly heterozygous: anemia (half-life of RBC = 15 days), equal amts HbS and HbC, sx similar to HbS w/ frequent retinal attachment due to capillary blockage and splenomegaly |
|
|
Term
|
Definition
Glu->Gln @ 121
mild anemia
doubly heterozygous: mild sickle cell anemia, electrophoretically identical to HbS |
|
|
Term
|
Definition
|
|
Term
Beta Thalassemia/Thalassemia Major/Cooley's Anemia
defect?
result?
dx?
syndrome?
tx |
|
Definition
Failure to synthesize beta chains
High percentage of HbF (30-90%) and HbA2, but little or no HbA
Ratio of HbA2 to HbA markedly increased
Children are normal at birth, sx begin during first year: stunted growth, mongoloid-like featuers, spontaneous fractures, high pigmentation, iron deposition of heart and liver, hepatomegaly and splenomegaly, death usually due to iron deposition in heart
chelation therapy to alleviate iron deposition - chelating agents administered to solubilize and prevent deposition of iron
bone marrow transplantation or gene therapy in future
blood transfusion can be counterproductive |
|
|
Term
Thalassemia Minor
defect?
result?
dx?
syndrome?
tx |
|
Definition
heterozygous form of thalassemia major
may not be a problem, but important in family planning
HbF usually 1-15%, HbA 8-10%
Often double heterozygous situations where pt is heterozygous Thalassemia and HbS, HbC, HbE |
|
|
Term
Alpha Thalassemias
defect?
result?
dx?
syndrome?
tx |
|
Definition
Due to inability to activate gene coding for alpha chain
defect of one alpha gene: alpha+ trait
two genes: homozygous a+ trait, a0 trait
three genes: HbH disease
four genes: Hydrops Fetalis (gene deletion) |
|
|
Term
Structure of normal Hemoglobins
A
A1C
A2
F
Gower 1
Gower 2
Portland
H
Barts |
|
Definition
A: α2β2 92% of adult Hb
A1C: α2(β-NH-glucose)2 5% of adult Hb; i/c in pts with diabetes
A2: α2δ2 2% of adult Hb; i/c in β thalassemia
F: α2γ2 fetal Hb (mo 3-9), i/c in β thalassemia & other disorders
G1/G2/Portland present in early embryo (through mo2)
H: β4 found in α thalassemia, low sol, nonfunctional
Barts: γ4 may comprise 100% of Hb in homo α thalassemia, nonfunct
|
|
|
Term
Hemoglobinopathies:
*HbA1C*
*carbonylhemoglobin*
*sulfhemoglobin, cyanhemoglobin*
caused by? |
|
Definition
HbA1C: long term increased glycemia
COHb: after CO poisoning
poisoning by H2S, HCN, or by cyanides |
|
|
Term
Hemoglobinopathies:
*HbC*
caused by?
composed of?
leads to? |
|
Definition
point mutation in both genes coding for beta chain
B6 glu -> lys
mild hemolytic anemia |
|
|
Term
Hemoglobinopathies:
*HbSC*
caused by?
composed of?
leads to? |
|
Definition
different point mutations in each gene coding for beta chain
B6 glu -> val
B6 glu -> lys
more severe PT than HbC (same as HbS) |
|
|
Term
Hemoglobinopathies:
*alpha-Thalassemia*
caused by?
composed of?
leads to? |
|
Definition
deletional mutations
inability to activate gene coding for alpha chain
decreased synthesis of alpha chains
anemia
accumulation of gamma4 (Hb Bart's) and beta4 (HbH), and beta chain precipitation
defect of one gene: alpha+ trait
two alpha genes: homozygous alpha0, alpha+ trait
three: HbH
four: hydrops fatalis |
|
|
Term
Hemoglobinopathies:
*beta-thalassemia*
caused by?
composed of?
leads to?
treatment? |
|
Definition
point mutations
decreased or absent synthesis of beta chains
high % of HbF and HbA2
little/no HbA
ratio of HbA2:HbA very i/c
children are normal at birth (high HbF)
sx during first yr: stunted growth, Mongoloid features, spontaneous fractures, high pigmentation, iron deposition in heart and liver, hepatomegaly, splenomegaly, death usually due to iron deposition in heart
anemia
chelation therapy
BM transplantation
gene therapy (in future) |
|
|
Term
Hemoglobinopathies:
*Methemoglobinemia*
caused by?
characterized by?
leads to?
diagnosis? |
|
Definition
Fe2+ -> Fe3+
defects can be in alpha or beta chain
stable complex forms b/t Fe3+ and O2
inability to bind O2
chocolate cyanosis
*can't transport O2*
abnormalities seen in heterozygous state
HbM won't separate from HbA in electrophoresis; dx using other methods |
|
|
Term
Developmental hereogeneity
-first 2 months of pregnancy
-month 2 through birth
-first few months of life |
|
Definition
major site of erythropoiesis is yolk sac
Hb Gower 1, Hb Gower 2, Hb Portland
alpha chain slowly starts to increase...
major site of erythropoiesis is liver, spleen
HbF
major site of erythropoiesis is BM
beta chain increases...
HbA |
|
|
Term
Abnormality in Hb due to point mutations of globin chain genes (majority are harmless; some cause disease)
1. replacement of proximal histidine by tyrosine:
2. mutations that form unstable hemoglobins:
3. mutations & O2 affinity
4. mutations that cause abnormal processing of ___ or in increase in degradation of ___________.
5. hemoglobins with reduced water solubility cause: |
|
Definition
1. replacement of proximal histidine by tyrosine: MAKES HEME GROUP INACCESSIBLE TO METHEMOGLOBIN REDUCTASE; CYANOSIS IN HETEROZYGOUS
2. mutations that form unstable hemoglobins: CAUSE HEMOLYTIC ANEMIA, AND INSOLUBLE PROTEIN AGGREGATES (HEINZ BODIES)
3. MUTATIONS CAN CAUSE INCREASED OR REDUCED O2 AFFINITY
4. mutations that cause abnormal processing of mRNA or in increase in degradation of OF ALPHA OR BETA CHAINS.
5. hemoglobins with reduced water solubility cause: SICKLING DISORDERS |
|
|
Term
|
Definition
both copies of Hb beta gene have an S mutation
all beta subunits are replaced by beta S |
|
|
Term
|
Definition
Glu->Lys @ 26
mild microcytic anemia |
|
|
