Arya Bagherpour

Book Summary over Easom’s Lecture on Thalassemia(A summary transcribed by Arya Navid Bagherpour the 1st (ANB1))…jk guys

The Hemoglobin genes are present in two gene clustersHemoglobin:

1. Consist of two pairs of nonidentical polypeptides, thus different hemoglobins can be formed by different combinations of these polypeptides.

2. The alpha-like genes are on chromosome 16 and the Beta-like genes are on chromosome 11. These gene clusters have some interesting features:

a) Structurally related genes are placed close together on the chromosome

b) The gene clusters contain pseudogenes (they are related structurally to the real genes but they cannot be transcribed and/or translated

c) The cluster on chromosome 16 contains two alpha genes of identical structure

Note, not all of the alpha and beta like globin genes are expressed at the same time. Look at the diagram

From looking at this, the epsilon and b-looking symbol are limited to the early embryonic stage, and the alpha and gamma chains prevail during fetal development

HbF: is the fetal hemoglobinHbA: is adult hemoglobin

HbA completely replaces HbF 4 months after the birth of the fetus

More than 400 different point mutations have been described in the globin genes-Most of these mutations are single amino acid substitutions that can be traced to a single base substitution in a gene. At least half of these mutations do not affect the function of the molecule sufficiently to cause disease. The changes that do affect oxygen transport varies according to the site and the kind of the amino acid substitution:

1. Mutations in the heme-binding pocket can cause methemoglobinemia: which replaces the proximal histidine with tyrosine; this makes heme inaccessible methemoglobin reducatase 2. Some mutations that affect the interface between the subunits lead to hemoglobins with abnormal oxygen-binding affinity: Hemoglobins can have increased oxygen binding affinity or lower oxygen binding affinity.3. Some point mutations lead to abnormal processing of mRNA, premature degradation of mRNA, or increased proteolytic degradation of the alpha or beta chain: These mutations can cause thallasemia-like diseases4. Some abnormal hemoglobins cause hemolytic anemia because they have abnormal physical properties.

The thalassemias are caused by reduced alpha or beta chain production1. This results in anemia2. Also, the polypeptide (alpha or beta) that is present in excess amounts forms

insoluble aggregates that are damaging to the cell and reduce its lifespan.3. The different types of thallasemia

a) alpha thalassemia: Relative or absolute deficiency of alpha chainsb) beta thalassemia: Relative or absolute deficiency of beta chainsc) Thalassemia minor: Heterozygous alpha or Beta thalassemia. Anemia

may be present but is very mildd) Thalassemia major: Homozygous alpha or beta thalassemia. Sever

anemia

Alpha Thalassemia is caused most often by large deletions:1. There are four rather than two alpha chain genes in diploid somatic cells. Most

patients with this disease have large deletions that remove one or both of the alpha genes. The diagram shows the effect of different gene deltions:

Explanation of diagram:A: one gene is deleted: asymptomaticB: Two genes deleted on different chromosomes: alpha thalassemia minor, very mild anemiaC: Two genes deleted on the same chromosome: alpha thalassemia minor, very mild anemiaD: Three genes deleted: Hemoglobin H disease, moderately severe anemia

- A beta 4 tetramer (hemoglobin H) is the predominant hemoglobin in patients with deltions of the three alpha genes. It is unstable causing it to denature gradually and form inclusion bodies in the cells. E. All four genes deleted: hemoglobin Barth’s disease, hydrops fetalis – fatal - Because alpha chains are required both before and after birth, the fetus is affected as well, and a complete lack of alpha chains is fatal before or at birth. Under these conditions, an abnormal hemoglobin of subunit gamma 4 (hemoglobin Barth’s) is formed that has a tenfold-higher oxygen affinity than hemoglobin A; thus it can’t function as an effected oxygen carrier

Many different mutations can cause Beta thalassemia1. Can be caused by large deletions, but most patients have single-base substitutions.2. Promoter mutations, splice site mutations, nonsense and frameshift mutations, and

a mutation in the polyadenylation signal all have been observed in different patients. Splice site mutations are very common

3. Beta not-thalassemia: mutations that result in a complete absence of Beta chains in the homozygous state. If left untreated, patients are likely to die of severe anemia and intercurrent infections during childhoold. If treated, patients are given regular transfusions of blood or packed erythrocytes, but are likely to die after the age of 20 due to iron overload. Desferrioxamine (a drug), an iron chelator forms soluble iron complex that can be excreted by the kidneys

4. Beta plus-thalassemia: mutations that cause a decrease in Beta chain synthesis, and homozygotes have a small number of Beta chains. Milder forms of this disaese, with classical expression intermediate between the classical minor and major forms, are called thalassemia intermedia

5. heterozygous state (betha thalassemia minor) is a benign condition that requires no treatment

6. The homozygous state is known as Cooley’s anemia: this is a severe disease. It is the most common type of severe thalassemia in the Mediterranean region and in many other countries. Severe anemia develops during the first year of life (this occurs bc fetal hemoglobin diminishes during this first year). This disease usually leads to a condition known as abortive erythropoiesis: RBC precursors contain aggregates of alpha chains, which appear abnormal to phagocytic cells which destroy them before they mature. Thus, the bone marrow responds to the anemia by working extra hard (the consequent expansion of red bone marrow leads to facial deformities).

High levels of fetal hemoglobin protect the patient from the effects of Beta thalassemia and sickle cell disease-A high level of HbF in adults is protective in all Beta chain abnormalities, including sickle cell disease.