Patients from the eastern province of Saudi Arabia who have sickle cell anemia have high circulating levels of fetal hemoglobin (hemoglobin F, 17 percent), and they therefore have a mild form of the disease. To examine the molecular basis of the elevated production of hemoglobin F, we searched for mutations in the promoter regions of the two hemoglobin F gamma-globin genes (Gγ and Aγ). The DNA sequences 450 bp (base pairs) upstream of both the Gγ and Aγ globin genes were normal except for a single-base cytosine-to-thymidine (C→T) substitution at -158 bp 5′ to the cap (preinitiation) site of the Gγ-globin gene of the high-hemoglobin-F chromosome. We searched for an association between this -158 C→T substitution and the production of hemoglobin F and Gγ in normal Saudis and Saudis with sickle cell disease or trait. The substitution was present in nearly 100 percent of the patients with sickle cell disease or trait, and in 22 percent of the normal Saudis. Homozygosity for this mutation had no demonstrable effect on hemoglobin F production in the normal Saudi population. We conclude that this mutation is not uniquely responsible for the increase in hemoglobin F in Saudi patients. It may nevertheless have an important role in regulating hemoglobin F production, but its expression is complex and requires interaction with additional factors, such as hemolytic stress or other molecular determinants, possibly linked to the sickle cell gene. (N Engl J Med 1987; 316:244–50.), RECENT evidence demonstrates that the hemoglobin S gene arose on multiple chromosomes and that it appeared on at least three occasions in geographically segregated regions of Africa.1,2 Genetically defined forms of sickle cell anemia have been associated with distinct clinical and hematologic characteristics.3 4 5 For example, patients from Senegal and Benin with sickle cell disease differ in regard to their peripheral-blood fetal hemoglobin (hemoglobin F) levels, ratios of Gγ to Aγ, and percentages of irreversibly sickled cells. In Senegal, the disease is milder, and both total and Gγ hemoglobin F are increased, providing further evidence that high levels of hemoglobin F….
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