DNA sequence variation associated with elevated fetal G gamma globin production.
The percentage of G gamma chains in the Hb F of SS patients and beta-thalassemia heterozygotes is generally 40%, but some have 60% to 70% G gamma. To test the hypothesis that DNA sequence variation 158 base pairs 5' of the G gamma gene is associated with this variation in G gamma values, DNA was analyzed using the restriction endonuclease Xmn I (gamma IVS-II probe). Xmn I recognizes the sequence from -157 to -166 only if T is at position -158. Individuals from five families had T at -158 for G gamma genes in both chromosomes, and the mean G gamma value was 69.7% +/- 4.6% (SD). For 13 families, individuals with T at -158 for the G gamma gene of one chromosome had a G gamma value of 60.6% +/- 5.7%. With one exception, lack of T at -158 was associated with low G gamma values (39.6% +/- 4.0%). In low Hb F G gamma-beta+-HPFH, the Xmn I site was seen 5' to both G gamma and A gamma genes, which suggests that T at -158 is associated with elevated Hb F; Pst I digestion showed that the A gamma gene T producer G gamma globin, which accounts for high levels of G gamma (87-88%). Calculations show that T at -158 is associated with a three- to 11-fold increase in production per G gamma gene, which is an order of magnitude less than that associated with the previously identified -202 C----G substitution of high Hb F G gamma-beta+-HPFH.
Gilman
J G
JG
Huisman
T H
TH
D000755:Anemia, Sickle Cell / Q000235:genetics; D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000032:analysis*; D004262:DNA Restriction Enzymes / Q000235:genetics; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis*; D007142:Immunoglobulin gamma-Chains / Q000096:biosynthesis*; D010375:Pedigree
D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D004247:DNA; D005319:Fetal Hemoglobin; D004262:DNA Restriction Enzymes