Sequences of G gamma, A gamma, and beta genes of the Greek (A gamma) HPFH mutant: evidence for a distal CCAAT box mutation in the A gamma gene.

Sequencing of the A gamma, G gamma and beta genes of a chromosome containing the A gamma Greek HPFH determinant revealed a mutation in position -117 of the promoter of the A gamma gene. The mutation is located in the distal member of the duplicated CCAAT box of the gamma gene. The finding suggests that the DNA region that includes the CCAAT box may play a role in the developmental control of gamma genes. It is suggested that the CCAAT box or its surroundings are involved in interactions between DNA and regulatory molecules whose binding results in silencing of gamma gene expression. Substitution at -117 of the A gamma gene may inhibit the interaction resulting in an A gamma HPFH phenotype. Sequencing of the beta genes of an A gamma Greek HPFH/beta thalassemia heterozygote was done to test whether beta gene expression takes place in cis to the A gamma HPFH determinant. The beta gene of the HPFH chromosome was found to be structurally normal. The beta thalassemia gene possessed a splicing site mutation known to create a beta thalassemia phenotype. These data provide structural evidence for expression of the beta gene in cis to the HPFH determinant.