alpha-Thalassaemia associated with the deletion of two nucleotides at position -2 and -3 preceding the AUG codon.

Publisher Website
Google Scholar
Abstract
The nucleotide sequence of 3 single .alpha.-globin genes resulting from a rightward 3.7-kb [kilobase] deletion is described. The .alpha. genes were isolated from the DNA of 3 subjects homozygous for this deletion, the 1st being in addition homozygous for the structural mutation .alpha.G Philadelphia (genotype -.alpha.G/-.alpha.G), the 2nd, heterozygous for this structural mutation (genotype -.alpha.A/-.alpha.G) and the 3rd homozygous for an .alpha.+-thalassemic gene (genotype -.alpha.+thal/-.alpha.+thal). The latter subject produced HbH in contrast to the 2 others. Whereas the 2 .alpha.A and .alpha.G genes are identical to the normal .alpha.1-globin gene (except for the .alpha.G point mutation), the .alpha.+thal gene has a deletion of the 2 nucleotides at position -2 and -3 preceding the ATG codon, and a fusion between the 5'' part of the normal .alpha.2 gene and the 3'' part of the normal .alpha.1 gene. Using a dot-blot assay, reticulocytes from the HbH subject contain at least as much .alpha.mRNA as reticulocytes from the 2 other subjects. In a transient expression system, the .alpha.+thal gene leads to normally spliced transcripts. The defective output of .alpha. chains by the .alpha.+thal gene, as evidenced by HbH production, results from a decreased efficiency of .alpha.-mRNA translation due to the 2 nucleotides deletion preceding the AUG codon.