G gamma beta+ hereditary persistence of fetal hemoglobin: cosmid cloning and identification of a specific mutation 5' to the G gamma gene.

Abstract

Hereditary persistence of fetal Hb (HPFH) is a benign condition in which the normal shutoff of fetal Hb (Hb F) production fails to occur. In the G.gamma..beta.+ type of HPFH, erythrocytes of adult heterozygotes contain .apprxeq. 20% HB F, which is almost exclusively of the G.gamma.-globin variety, without increased levels of .gamma.-globin chains from the nearby A.gamma.-globin gene. Unlike some forms of HPFH, no major deletions in the globin gene cluster have been found by genomic blotting in the G.gamma..beta.+ variety. A family with this condition, from which cosmid clones of the .beta.-globin gene cluster from the G.gamma..beta.+ HPFH allele have been obtained, is reported. Sequencing around the fetal genes identified a point mutation 202 base pairs 5'' to the G.gamma.-globin gene that is present in genomic DNA of 3/3 unrelated individuals with G.gamma.B+ HPFH but in none of more than 100 non-HPFH individuals. Although the mutation could represent a tightly linked polymorphism, its location in a region suggested by recent data to be important in tissue-specific control of gene expression suggests the possibility that the -202 mutation accounts for the phenotype. The sequence created resembles elements of other eukaryotic promoters known to be important for efficient transcription.