Hemoglobinopathies Flashcards
defective globin switching
persistence of fetal hemoglobin
microcytosis
small cells
hydrops fetalis
fetal death due to complete lack of alpha hemoglobin genes
What is the embryonic hemoglobin?
HbG
The tense hemoglobin state is the ______ state, while the relaxed state is _______ and planar.
deoxygenated; oxygen-bound
Where are most structural hemoglobin variants found?
in the Beta-globin chain
hemoglobin H disease
severe anemia because only 1/4 alpha globin gene is functional
What is non-covalently linked in between the globins?
iron and a heme group
How many genetic variants of hemoglobin are known?
600
What is the fetal hemoglobin?
HbF (alpha 2 gamma 2)
How do you test for sickle cell?
1) DNA sequencing with PCR or electrophoresis 2) southern blot
Thalassemia minor
mild phenotype; doesn’t req transfusions
In beta-thalassemia, defects are seen _____.
postnatally only
How are hemoglobin C and hemoglobin S different?
Same codon, different mutations, different phenotypes
HbKemsey has _____ O2 binding while hemoglobin Kansas has ______ O2 binding.
too tight; too weak
Which form of hemoglobin is the best oxygen carrier?
alpha-beta
Where is hemoglobin synthesized?
in the bone marrow
How many copies of the beta globin gene are there?
1
What is the major adult hemoglobin?
HbA
In HbKempsey, the O2 binding affinity is _____, so _____ O2 is delivered to the tissues, and to compensate, red blood cells are ________. This condition is called _______.
higher; less; overproduced; polycythemia
The 5’-3’ ____ order of genes within each cluster coincides with the _____ order of their expression during development.
spatial; temporal
structural variants/qualitative hemoglobinopathies
mutations that alter the globin’s properties without affecting its synthesis
Phenotypically, having 2 out of the 4 alpha globin genes results in _____.
mild anemia
How many oxygens does each globin bind?
one each; 4 per molecule
hypochromia
pale blood cells
What is hereditary persistence of fetal hemoglobin?
benign conditions that impair the perinatal switch from gamma to beta globin synthesis (high GbF in adults)
Beta-thalassemia is most often caused by _______.
point mutations in the beta-globin gene
Alpha-thalassemia is a ______ of alpha-globin and an excess of _____.
low or no amount; beta and gamma
thalassemia major
beta-zero; no beta proteins being produced
How many identical copies of the alpha globin gene are there on each chromosome?
2
What does the alpha cluster encode?
zeta- alpha2- alpha1
Where is embryonic hemoglobin made?
in the yolk sac
What do structural variants of hemoglobin do?
alter O2 binding
What does the beta cluster encode?
epsilon- gamma G-gamma A- delta- beta
Why is delta hemoglobin transcribed less?
it has a weaker promoter
thalassemias
low to no synthesis of one globin chain
What is globin switching?
transitioning between hemoglobins as development progresses
What kind of globin is expressed in fetal development?
gamma
What are the 3 genetic disorders of hemoglobin?
1) structural variants 2) thalassemias 3) defective globin switching
What is a pseudogene?
a gene that doesn’t make a protein
Why does globin switching occur?
HbF in fetal blood is better suited to bind O2 at the placenta than HbA (lower pO2), which binds O2 better in the lung (higher pO2)
hemolysis
destruction of blood cells
Where is fetal hemoglobin made?
in the liver
Why is beta globin often affected by mutations?
there are only 2 copies of it, not 4 like alpha
Complex beta-thalassemia is caused by ____.
large deletions
In sickle cell anemia, a glutamate at position 6 is changed to ______, which changes the position that Mst II cleaves at, making a ______ protein than the wildtype.
valine; larger
What is the minor form of adult hemoglobin?
HbA2 (alpha 2 delta 2)
What is the solubility of hemoglobin S?
normal when oxygen is bound, but only 20% of normal when unbound
What happens when the LCR is knocked out of the beta cluster?
beta thalassemias result and alpha-globin chains precipitate
Alpha-thalassemia is occasionally caused by _______.
deletions in the LCR or the beta-gene cluster
In HbKansas, the O2 binding affinity is _____, so _____ O2 is delivered to the tissues, and ______ occurs.
decreased; less; cyanosis
Alpha-thalassemia is caused by _______.
a deletion of the alpha-globin gene(s)
Where is the alpha globin gene cluster located?
chromosome 16
Which is the first globin expressed?
epsilon
What does LCR stand for?
locus control region
Beta-thalassemia is a ______ of beta-globin and an excess of ________.
low or no amount; alpha-globin
Hemoglobin is a tetramer of 2 _____ polypeptides and 2 _____ polypeptides.
alpha; beta
What is the LCR of hemoglobin?
the promoter region about 20kb away from the first hemoglobin gene that regulates sequential transcription of all the genes
In alpha-thalassemia, defects are seen _____.
fetally and postnatally
Where is the beta globin gene cluster located?
chromosome 11
