Saturday, November 10, 2012

STRUCTURAL HEMOGLOBIN VARIANTS


STRUCTURAL HEMOGLOBIN VARIANTS (Haemoglobinopathies)

Hemoglobinopathies, the most common single gene disorder and are structural Hb variants arising from mutations in globin genes, which results in alteration in normal amino acid residues in one or more globin chains.

Over 900 qualitative variants have been identified in which the hemoglobin molecule is structurally and in some case functionally altered. These arises most commonly due to single amino acid substitutions, but also insertion or deletion of amino acids and polypeptide fusion as  result of recombination between globin genes, e.g. Hb Lepore. The most common structural variants are haemoglobins S, C, Dpunjab and E which affect worldwide.

Hb variants are named using letter (Hbs S, D, E, etc), the family name of the index case (Hb Lepore), the place of discovery of variant or place or origin (Hb Edmonton) or the name of the river (Hb Saale). 


Hb variants are classified according to the type of mutation.
·         Single point mutations in α-globin chain give rise to a suubstitution of one amino acid residue. E.g. substitution of valine for glutamic acid at position 6 in the A helix of the β-globin chain resulting HbS (sickle cell disease).

·         Deletion of Hb variants arises from the deletion of one to five amino acid residues in the globin chain. E.g Hb Vicksburg (β75(E19)Leuà0) is an example where Hb having a deletion of leucine in position of 75 of the β-chain.

·         Insertion Hbs arise from an insertion of one to three amino acid residue into the globin chain. Hb Grady is an example having an insertion of 3 amino acid residue (Glutamine-phenylalanine-threonine) between position 118 and 119 of α-chain.

·         Deletion-insertion Hbs arise from the deletion of a portion of normal amino acid residue sequence and the insertion of another sequence which resultant lengthening or shortening of the globin chian. E.g. Hb Monteral in which the 3 nomal amino acid residues between positions 72 and 76 of the β-globin chain are replaced with a four amino acid residue.

·         Elongation Hbs results from a single base pair mutation or frameshift at the 3’ end of exon 3 or 5’ end of exon 1 of the α2 or the β-globin chain. The elongation Hb, Hb Constant spring (found in constant spring district of jamaica), has an additional 31 amino acid residue joined at position 142 (the carboxy terminal) of the α-chain.

·         Fusion Hbs result from the fusion of either α or β-globin chain with a portion of another globin chain. Hb Lepore-Hollandia results from the fusion of the first 22 amino acid residue of the δ-chain, with tha amino acid sequence from position 50 onward of normal β-globin. 


 In α-chain variants, the variant usually forms <25% of total Hb since the mutation occurs only in one of the four genes coding α-globin chain. For β-chain variants in heterozygous state, the variant forms 25%-50% of total Hb. This is used to categorized an unknown Hb variant as either an α- or β-globin chain variant. 
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