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8. Beskrive den molekylære baggrund for sygdomme der skyldes hæmoglobin deffekt
Devlin, s.394 – cc. 9.6
Devlin, s.112 – cc.3.3
Devlin, s.238 – cc.6.1
Devlin, s.239 – cc.6.3

Diseases called by mutations in the hemoglobin gene are called hemoglobinopathies. There are over 400 mutant hemoglobines, usually causing instability in the hemoglobin structure.

A hemoglobin molecule consists of four polypeptide chains, two each of two different amino acid sequences. The major hemoglobin found in adults is HbA₁, consisting of 2 x α and 2 x β chains.  

I will take two examples of hemoglobinopathies caused on the molecular level: sickle-cell anaemia and thalassemia.

SICKLE-CELL ANAEMIA

On molecular level, the disease is caused by a missence mutation, which happens in the second position of the codon nr.6 in the β-globin gene of HLA₁.

An A is exchanged for U in either GAA or GAG codon for glutamate (negatively charged). The codons are changed into GUA or GUG which code for valine (nonpolar).

So glutamate is exchanged for valine in position nr.6 of the β-globin chain in HbA1. The newly created mutated hemoglobin, in which the negative side chain is replaced for non-polar side chain, is called hemoglobin S – HbS.

The hydrophobic valine interacts with valine of other HbS chains, creating precipitation of hemoglobin within the red blood cells, giving them sickle-shape. These abnormal blood cells have a high rate of haemolysis and lack of elasticity when they pass through small capillaries (that become clogged by the abnormal shaped cells).

Only homozygot individuals (having the mutation on both chromosomes) exibit the disease.

A heterozygot individual that has 50% HBA₁ and 50% HbS exsibits no symptoms.

THALASSEMIA

Thalassemias are genetic defects in the coordinated synthesis of α and β-globin peptide chains. The severity of symptoms leads to the classification of the disease into thalassemia major or minor.
 

α-thalassemia – in the diploid genome, there are all in all 4 genes that encode for α-globin, 2 on the maternal chromosome 17 and 2 on the paternal. Many instances of thalassemia arise from deletition of two, three or all four α-globin genes.  The clinical severity of the symptoms increases with the number of the mutated genes.

α- thalassemia can also appear due to a mutation in the stop-codon of a gene creating abnormally long proteins.

β-thalassemia – can result from a wide variety of mutations. Known events include:

·          mutations leading to frameshifts in the β-globin coding sequence

·          non-sense mutations leading to premature termination of peptide synthesis

·          mutations affecting the biosynthesis of mRNA

·          mutations in the promoter region of the gene, leading to inefficient transcription

·          aberrant processing of the mRNA transcript – incorrect splicing or error in polyadenylation

The β-globin gene is located on chromosome nr.11 and unlike the α-one, it only has one copy in the haploid genome.   

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