The C → G transition in the α2-globin gene of a normal αα-chromosome is responsible for the Hb G-Philadelphia variant in Sardinians

Sequencing of alpha-globin genes of 18 Sardinian heterozygotes for the Hb G-Philadelphia [alpha68(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 alpha2-globin gene (alpha(G)alpha/alphaalpha). Two heterozygotes with level of about 37% were the carriers of the same mutation on the same alpha2 gene, and of the alpha2alpha1 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 alpha2 gene of a normal alphaalpha arrangement. The identification of the C-->G mutation on the normal alphaalpha 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.