The haemoglobin molecule and thalassaemia Flashcards
(40 cards)
- function of RBC
- average number of RBCs
- how much Hb do they contain?
- properties of RBCs
Carry oxygen from lungs to tissues Transfer CO2 from tissues to lungs 3.5-5 x 1012 /L Contain haemoglobin (Hb) Each red cell contains approximately 640 million molecules of Hb Do not have nucleus or mitochondria
- normal conc of Hb in adults
- how much is produced and destroyed every day?
- how much iron does each gram of Hb contain?
Found exclusively in RBCs
MW 64-64.5 kDa
Normal concentration in adults:120-165g/L
Approximately 90 mg/kg produced and destroyed in the body every day
Each gram of Hb contains 3.4mg Fe
when does haemoglobin synthesis occur?
Synthesis occurs during development of RBC and begins in pro-erythroblast:
65% erythroblast stage
35% reticulocyte stage
difference between reticulocyte and erythroblast
reticulocyte- immature RBC not containing a nucleus
erythroblast- immature RBC containing a nucleus
what is the basic structure of haemoglobin
It is a composite molecule consisting of FOUR haem groups and FOUR globin
chains
Each haem group is bound to an Fe2+
Each haemoglobin molecule can bind
FOUR oxygen molecules
where are Haem and Globin synthesised?
- Haem (synthesised in mitochondria which contain the enzyme ALAS)
- Globin (synthesised in ribosomes)
where can haem also be found?
also contained in other proteins eg myoglobin, cytochromes, peroxidases, catalases, tryptophan
how is globin synthesises?
Various types (alpha, beta, delta, gamma) which combine with haem to form different haemoglobin molecules
Eight functional globin chains, arranged in two clusters:
what chromosomes are used for globin genes?
b- cluster (b, g, d and e globin genes) on the short arm of chromosome 11
a- cluster (a and z globin genes) on the short arm of chromosome 16
why is the arrangement of globin genes unusual?
this is an exception to the one gene=one protein hypothesis. There are TWO alpha globin genes from each parent, so in total there are FOUR alpha globin genes
describe globin gene expression and switching
– Globin Gene Expression and Switching:
§ a - is made relatively early and stays high throughout.
§ b - is equal and opposite to g and becomes dominant after birth.
§ g - is equal and opposite to b and is dominant pre-natal.
§ d - production begins mid-natal and remains low forever.
§ e and z - is equal and opposite to a and levels drop ~0 after 8 weeks.
how is haemoglobin synthesised?
- Haem:
a. Transferrin transports the ferrous to the RBC or the ferrous is liberated from the ferritin molecules.
b. Glycine, B6 and Succinyl CoA create delta-ALA which then undergoes a few moderations outside the mitochondria and then passes back in as proto-porphyrin.
c. Proto-porphyrin à haem which binds with the globins. - Globin:
a. Amino acids are used in ribosomes to create the globin chains. - Haemoglobin:
a. Globins and haem associate.
what is the most abundant haemoglobin?
§ HbA (a2b2) is the most common – 96-98%.
§ HbA2 (a2d2) is the second most common – 1.5-3.2%.
§ HbF (a2g2) is the least common – 0.5-0.8%.
what is the globin structure (primary, secondary and tertiary)
§ Primary - a (141aa), non-a globins (146aa).
§ Secondary – 75% of a and b chains show a helical arrangement.
§ Tertiary – approx. sphere with a hydrophilic surface and a hydrophobic core, contain a haem pocket.
what is the difference between oxygenated and deoxygenated haemoglobin?
§ Haemoglobin has the highest affinity to oxygen when the binding is loose (cooperativity) – more O2 means greater binding of O2.
what does 2,3 DPG do to the affinity for oxygen
2, 3-DPG is made by muscle cells to increase dissociation of oxygen.
describe the oxygen dissociation curve
§ Sigmoid shape – binding of one molecule facilitates binding of another.
o Greater unloading across a range of low pressures.
what does the position of the ODC depend on?
Position of the ODC depends on – 2, 3-DPG conc., pH, CO2 conc., structure of Hb.
define P50
P50 = 26.6mmHg (partial pressure of O2 at which Hb is half saturated with O2).
define Haemoglobinopathies
Haemoglobinopathies – a genetic disorder characterised by a defect of globin chain synthesis.or structural variants of haemoglobin
how can thalassaemia be classified?
o Globin type affected.
Clinical severity:
§ Minor or “trait”.
§ Intermedia.
§ Major
how many alpha and beta clusters are there?
There are 4 alpha clusters in total (alpha1 and alpha2 on each chromosome 16) but only 2 beta clusters.
what is beta thalassaemia?
autosomal recessive inheritance.
§ Deletion or mutation in b-globin chains – reduced or absent production of beta-globins.
§ Inheritance:
o When 2 beta trait have a child, there is a 25% chance of a beta-major offspring.
o Beta Thal Intermedia can also come about when one partner has a beta+ mutation which is less severe.
§ b0 = deletion of one beta globin-encoding gene.
§ b+ = mutation of one beta-globin encoding gene.
what laboratory diagnosis can be used to diagnose beta thalassaemia?
FBC – microcytic Hypochromia and increased RBCs relative to Hb.
Film – Target cells, Poikilocytosis (shape change) but NO anisocytosis (unequal size).
Hb EPS (electrophysiology studies)/HPLC (high performance liquid chromatography): o a-thal – normal HbA2 and HbF, ±HbH. o b-thal – raised HbA2 and HbF.
Globin chain synthesis/DNA studies:
o Genetic analysis for b-thal mutations and Xmn1 polymorphisms (b-thal) and a-thal genotypes (in all cases)
