The C-->G transition in the alpha 2-globin gene of a normal alpha alpha-chromosome is responsible for the Hb G-Philadelphia variant in Sardinians.

Abstract

Sequencing of alpha-globin genes of 18 Sardinian heterozygotes for the Hb G-Philadelphia [alpha 68(E17)Asn-->Lys] variant, with four active alpha genes and circulating level of the variant of about 27%, showed the AAC-->AAG change at codon 68 of the alpha 2-globin gene (alpha(G)alpha/alpha alpha). Two heterozygotes with level of about 37% were the carriers of the same mutation on the same alpha 2 gene, and of the alpha 2 alpha 1 hybrid gene, because of the 3.7-kb deletion, in trans (alpha(G)alpha/-alpha(3.7)). In Black people, the same C-->G mutation occurs on the hybrid gene (-alpha(G)3.7), whereas in Caucasians the Lys for Asn change is because of the C-->A transversion occurring on the alpha 2 gene of a normal alpha alpha arrangement. The identification of the C-->G mutation on the normal alpha alpha chromosome points to an undescribed genotype for this rather common variant, which is probably because of the high rate of recombination between the duplicated alpha-globin genes.