preview:● Haemoglobin is a tetramer made up of 4 globin polypeptide chains and each of them has a single haem group in the middle.
● When iron is bound to the oxygen the haem group is red in colour however when it lacks oxygen it is a blue and that's called deoxyhaemoglobin.
● Haem is made ...
● Haemoglobin is a tetramer made up of 4 globin polypeptide chains and each of them has a
single haem group in the middle.
● When iron is bound to the oxygen the haem group is red in colour however when it lacks
oxygen it is a blue and that's called deoxyhaemoglobin.
● Haem is made in the liver, muscles and also your red blood cells whereas globin production
is localised to the red blood cell and humans can synthesise six different types of globin at
different stages of life.
● Ontogeny means where things take place, the ontogeny of haemoglobin is described in this
figure.
● The makeup of the globin tetramer evolved from the embryo to the foetus and the adult.
Embryonic haemoglobin exists for the first 12 weeks, and it consists mainly of alpha, zeta,
epsilon and gamma globulin chains and these makeup haemoglobin gower 1, portland and
gower 2. The transitions happen in an orderly and regulated manner.
● Why do we need all these different types of haemoglobin? The embryo and foetus are faced
with the challenge of obtaining oxygen from the placenta not the lungs and that means it is
ultimately from the maternal circulation so embryonic and foetal haemoglobin have to be
able to take oxygen from the haemoglobin of the mother, the foetus and the neonate face a
similar challenge as they developed which is partly solved by introducing delta globulin in
the haemoglobin molecule in the place of the gamma globulin.
● By about three to six months, you see the major switch from foetal to adult haemoglobin in
the neonate so after birth and the beta globin slowly replaces all delta, and the gamma
globulin will replace all the alpha globulin and that leaves us with our 2 alpha and 2 beta
chains.
● This is going to form the basis of what we discuss in the next couple of slides.
● Now we've discussed the structure of haemoglobin in a healthy adult we know that the adult
globin genes HbA and HbB code for different combinations of globular proteins such as alpha
globulin and Peter globulin. In health the different variants of the globulins lead to different
types of haemoglobin, so we get HbA, HbA2 and HbF. Mutations in these genes will give rise
to the different amounts of haemoglobin synthesised and these cause certain anaemias. This
type of abnormality is called a haemoglobinopathy.
● The principle two hemoglobinopathies that you will hear of are your sickle cell and
thalassemia, they almost always inherited and to date there are over 1800 variants of these.
● Both types result from a mutation of a healthy globin gene with a consequent alteration in
the amino acid composition or the amount or a particular globulin chain – so they affect the
ability of haemoglobin to transport oxygen, if that happens, they are unable to provide that
tissue with sufficient oxygen for their needs and then that's why we get these symptoms of
anaemia.
, 4. Thalassaemia and Sickle Cell Disease
● Some people end up being asymptomatic whereas others have a severe compromise of their
quality of life.
● 1 – the most common hemoglobinopathies include qualitative abnormalities in the beta
globin chain so that's a point mutation that changes the amino acid composition of the
protein and examples of this are sickle cells so HbS, HbC, HbD and HbE.
● There is no shortage of globin protein, the abnormality lies in the amino acid component.
● 2 – the other type represents a quantitative defect so we get a reduced rate of synthesis of
normal alpha or beta globin chains so here we have point mutations that change the amount
of globin chains that are produced, the reason they are called quantitative is that they're
reducing the mass of the globin protein so lots of amino acids are going to be missing and
then this is the category that our alpha and beta thalassemias fall into.
● Both arise from mutations in haemoglobin genes, and both will lead to reduced oxygen
carrying capacity of our red blood cells.
● This shows the geographical distribution of the thalassemias and it just really emphasises
that they can be found globally but there are certain areas are prevalence.
● How do we classify our haemoglobinopathies? Everyone is a classified based on the number
and type of genes that are abnormal, we have 4 alpha globin genes and 2 beta globin genes
so if for example both genes carry the mutation e.g., in sickle cell disease and the person is
described as homozygous however if only one gene carries a mutation, the individual is
called a heterozygote and these people are carriers and the condition is called trait and is
generally clinically less severe.
● There is an excess of unpaired chains in thalassemia because they've got nothing to bind to.
● Chromosom e 16 carries two copies of other alpha globin genes HbA and because each of us
have two copies of chromosome 16 we end up with 4 alpha globin genes overall and the
majority as the globin gene mutations are deletions and the number of deletions determines
the severity of the disease.
● In the image on the right-hand side, we've got two parents that are carriers and we’ve gone
through each of the pregnancies below.
● There's a 25% chance that a child might be unaffected completely so they'll inherit all the
good alpha globin genes, there is a 50% chance that the children will be silent carriers of
alpha thalassaemia so they will inherit one defective alpha globin gene and there is a 25%
chance that the child will be born with alpha thalassemia, so they’ve got two of the genes.
● We will go through the number of deletions at the next slide.
● This causes defective foetal and adult haemoglobin, so this haemoglobin is unable to
transport oxygen to the organs and that's what causes the clinical presentation however it's
important to remember in alpha thalassemia the abnormal cells don't go out of shape, they
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