G y and ly Globin Genes are Identical from -471 of the Promoter Midway through yIVSII in a Benin is Haplotype Associated with Elevated Fetal Hemoglobin

Summary In seven kindreds in which sickle cell (SS) patients had elevated (>12%) fetal hemoglobin (Hb F), Milner and colleagues reported that a determinant for elevated Hb F and elevated F cells was linked to the I3s gene. Independently, the Senegal (SEN) Ps haplotype has been found in association with elevated Hb F in SS and IB-thalassemia patients. We have used the kindreds of Milner and colleagues to characterize further the association of haplotype and y gene DNA sequence variation with Hb F expression. For the largest kindred, Wi, all four SS had high (>14%) Hb F and both SEN and Benin (BEN) haplotypes. Two AS cases carrying SEN had low Hb F and low F cells, while three AS and one CS carrying BEN had elevated Hb F and elevated F cells; only one AS carrying BEN had low Hb F and low F cells. In order to look for genetic alterations that could account for the elevated Hb F of kindred Wi, we sequenced both the Gy and )'Y genes of the Wi BEN haplotype. The data showed largely identical Gy and )iy genes which may have been generated by two gene conversions: the Ay promoter was like that of Gy 3' to -471, while the Gy IVSII was like that of "y in its 5' half. In addition, three new mutations were found in yIVSII. yIVSII sequence variation shown by this and other studies results in various distributions of the (A/C)CACCC motif for the binding of regulatory proteins, and we hypothesize that this may account for some of the variability of Hb F expression in SS patients.

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