Fetal hemoglobin in sickle cell anemia: relation to regulatory sequences cis to the beta-globin gene. Multicenter Study of Hydroxyurea.
Very different fetal hemoglobin levels among adult sickle cell anemia patients suggest genetic modulation of gamma-globin gene expression. In sickle cell anemia, different fetal hemoglobin levels are associated with distinct beta-globin gene haplotypes. Haplotype may be a marker for linked DNA that modulates gamma-globin gene expression. From 295 individuals with sickle cell anemia, we chose for detailed studies 53 patients who had the highest or the lowest fetal hemoglobin levels and 7 patients whose fetal hemoglobin levels were atypical of their haplotype. In these individuals, we examined portions of the beta-globin gene locus control region hypersensitive sites two and three, an (AT)x(T)y repeat 5' to the beta-globin gene, a 4-bp deletion 5' to the A gamma T gene, promoters of both gamma-globin genes, 5' flanking region of the G gamma-globin gene, and A gamma-globin gene IVS-II. Of the regions we studied all polymorphisms were always haplotype-linked and no additional mutations were present. This suggested that variations in these areas are uncommon mechanisms of fetal hemoglobin modulation in sickle cell anemia. Whereas unexamined cis-acting sequences may regulate gamma-globin gene transcription, trans-acting factors may play a more important role.
Lu
Z H
ZH
VA Medical Center, Jackson, MS 39216, USA.
Steinberg
M H
MH
D000755:Anemia, Sickle Cell / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005319:Fetal Hemoglobin / Q000235:genetics*; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D008969:Molecular Sequence Data; D012045:Regulatory Sequences, Nucleic Acid
D017931:DNA Primers; D005914:Globins; D005319:Fetal Hemoglobin; D006918:Hydroxyurea