Mutations of the a globin genes causing a thalassemia

Deletions of one or both a globin genes on a chromosome are the commonest cause of a thalassemia (Higgs, 2001). The original duplication that gave rise to two a globin genes has been well conserved and since these blocks lie adjacent to each other, it is not uncommon for misalignment to occur between the a1 gene of one chromosome with the a2 gene of the other, during meiosis. Crossing over would then result in either a chromosome with three a genes (which has no hematological consequences on its own) or one with a single a gene. Depending on the precise site of the cross over, the deletions differ slightly in size, with the two commonest forms losing 3.7 or 4.2 kb of sequence (depicted as -a37, -a42, respectively). These deletions are extremely common in the Mediterranean, Africa, the Middle East and Southern and South East Asia; in some populations a single a gene chromosome is more common than one with two (see below). Heterozygotes for this mild form of a thalassemia show minimal red cell changes while homozygotes have smaller red cells containing less hemoglobin than normal but are not clinically affected.

Larger deletions remove both a globin genes on the same chromosome. Most of these are rare but those found in the Mediterranean (-MED) and in South East Asia (-SEA) reach polymorphic frequencies. Heterozygotes for these deletions have a similar phenotype to homozygotes for the single gene deletion, since both still have two functioning a genes. Compound heterozygotes with only one a gene (-/-a) show more severe red cell abnormalities, including the presence of HbH, and a clinical course that varies from quite mild to fairly severe anaemia. Homozygotes for the double gene deletion (-/-) are severely anemic in utero, developing hydrops fetalis and usually dying shortly before or immediately after birth.

Deletions that remove the a globin gene regulatory element but spare the structural genes themselves also cause a thalassemia. These are rare conditions in which a mRNA is reduced to <1% of normal and are important for demonstrating the essential role of the HS -40 element.

Although gene deletions are by far the most common cause of a thalassemia, point mutations may also result in this condition. Mutations that cause frameshifts, affect RNA splicing, alter the poly(A) addition signal or modify the translation initiation sequence have all been described. An additional group of mutations affect the chain termination codon of the a gene, resulting in read-through into the 3' untranslated region of the RNA, destabilizing it. One of these termination mutants (Hb CS) is a common form of a thalassemia in South East Asia.

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