Flashcards in Normal and abnormal Hemoglobin Deck (59):
What is the most common type of Hb in humans? What are the two chains that comprise this?
True or false: all of the heme groups in the Hb tetramer bind oxygen with equal affinity
What is responsible for the sigmoidal shape of Hb oxygen binding curve?
Increased affinity of Hb to binding oxygen as each subunit binds an oxygen molecule
The second most common form of Hb has what subunits?
HbA2 = alpha and delta
What are the three Hbs that are found early in embryonic development? What are each Hbs subunits?
Hb Gower (zeta2, epsilon 2)
Hb Gower 2 (alpha2, epsilon2)
Hb portland (zeta2 gamma2)
What happens to gamma globin levels as development progresses? Beta?
Gamma starts high, end low
v.v. for beta
What is the major Hb of the fetus? What subunit does it have instead of beta?
What is the amino acid change in HbF compared to HbA? What subunit is this on? What is the consequence of this?
S instead of a H on gamma chain = cannot bind 2,3 BPG d/t no more positive charge
What are the two alpha-like globins?
alpha and zeta
The alpha like globins are found on which chromosome?
The beta like globin chains are found on what chromosome?
What caused the different alpha/beta like globins to arise?
gene duplication events
What are the locuses upstream of the alpha and beta like globin chain DNA?
Hs-40 for alpha
LCR for Beta
What are the pseudo gents that lie between the seta and alpha codons on the genes?
multiple mutated globins that are non-functional
How are thalessemias brought about?
Gene duplication/mutation events bringing about nonfunctional globins
What are the two major distinction of hemoglobinopathies?
What exactly are thalassemias?
imbalanced synthesis of alpha and beta globin chains
Unstable Hbs tend to form what? What generally happens to them?
oxidized to methHb
What is hemichrome?
Large aggregates of unstable Hb proteins aggregate to form what?
What are the three Hbs that cause major health problems?
What is the major symptom associated with methemoglobin?
What is the important of the association between the alpha and beta subunits?
Stabilize the T form
What is the order of alpha, zeta, and psi on the alpha chain DNA?
What is the order of beta, delta, gamma, epsilon, and psion the beta chain DNA?
What is the amino acid change in HbS? What is the significance of this?
E goes to V in thebeta globin chain
deoxygenated HbS polymerizes
What does it mean to have the sickle cell trait, vs having the sickle cell disease?
trait = heterozygous
disease = homozygous
What is the basis for treating sickle cell anemia with hydroxyurea?
Increases the expression of HbF
What is the amino acid substitution for HbC? What is the consequence of this?
E to a L in the beta globin chain
HbC is less soluble and precipitates, causing hemolytic anemia
True or false: it is not uncommon to find patients that have both HbS and HbC
What is the amino acid change in HbE? What is the consequence of this?
E to a L in beta globin chain
Beta globin chain is not synthesized effectively, causing thalessemia
What are the symptoms of HbE?
Heterozygotes = asymptomatic
Homozygotes = mild anemia/hypochromia
What are alpha naught and beta naught thalessemias?
Where neither alpha nor beta chains are produced at all from the affected locus
What are alpha+ and beta+ thalessemias?
Reduced amounts of globin chain produced from the affected locus
How many alpha genes are present on chromosome 16?
What are the most common thalassemias?
alpha and beta types
Why are alpha thalessemias particularly concerning?
Found all the way through development (Hb Gower, fetal and adult Hbs)
What happens when there are three functional alpha globin genes, and one defective gene?
no clinical signs
What happens when there are two functional alpha globin genes, and two defective genes?
What happens in development when there is only 1 functional alpha globin gene? What are the Hbs that result from this like?
Gamma4 tetramers (Bart's Hb) results, which then go to beta4 tetramers.
Very high oxygen binding capacity
What happens when there are no functional alpha globin genes?
Only embryonic, Gower 1 Hbs are produced, causing Bart's hydrops fetalis (fatal)
What is Bart's hydrops fetalis?
4 defective alpha globin genes leads to Gower/portland Hbs, and eventually death
What is Hb H? What disease is the a part of? What is the oxygen binding like?
Produced when there is only 1 functional alpha globin produced. Made of beta4 globins. High oxygen binding capacity
What is the amino acid that blocks the oxygen binding site in the beta subunits, and is only moved when both alpha subunits have bound oxygen?
What are the three hemoglobinemias that can result if there is structuratl variation in Hb?
Lower Oxygen affinity
What is Bart's Hb? What disease does it form in?
gamma4 tetramer which forms if there is only 1 functional alpha globin gene
What is the cause for the development of thalassemias?
Deletion brought about by misalignment of the DNA registers during homologous recombination
What is the genetic basis for Hbconstant spring?
Point mutation that replaces a T with a C in the normal stop codon, causing a read through the stop
What is the impact of Hn constant spring? Why is it not more impactful?
alpha+ thalassemia anemia
The aberrant mRNA is only a small fraction, and is degraded quickly
How many genes are there for beta chains in a normal diploid cell? What happens when one becomes mutated and non-functional? Two?
one non-function = typically asymptomatic, with mild anemia
Two = severely affected
Why is there more HbA2 in pts with beta thalessemias?
Upregulation since HbA2 has alpha 2 globins
What is the genetic basis for Lepore Hb?
Crossing over lead to delta-beta gene, with deletion of some of both
What gives rise to the hereditary persistance of fetal Hb?
Loss of beta and delta Hb genes
What are the symptoms of Lepore disease?
Poor globin chain function, but usually asymptomatic
How are point mutations generated in beta thalassemias?
Incorrect splicing leads to the production of a non-functional gene
True or false: eletrophoresis to screen neonates for Hemoglobinopathies is very specific/sensitive, but very expensive
False- very cheap, but very insensitive
What is the basis for isoelectric focusing?
gel eletrophoresis with a gel that has a pH gradient. The proteins will stop at the ph=pKa point
What is the basis for PCR-RFLP?
Adding restriction endonnucleases will cut the normal variant of the gene, but not the abnormal one. Thus if you have long DNA chains resulting from the PCR, then you have an abnormal result