Human G gamma and A gamma globin gene constructs containing the 3' A gamma enhancer show persistent fetal expression...

Transgenic mice were produced from two 13 kb constructs containing the fetal (gamma) globin genes. Each construct consisted of a G gamma globin gene linked to one of two alternative A gamma genes. The first construct contained a normal G gamma gene plus an A gamma gene with the -198 T-->C hereditary persistence of fetal haemoglobin (HPFH) mutation. In the second, a normal G gamma gene was linked to a A gamma gene with a -222 to -225 four base pair deletion in the promoter. This latter mutation has been associated with low A gamma expression in humans. Both A gamma genes in these constructs also contained the 3' flanking enhancer. The two different constructs showed expression throughout gestation from day 11 yolk sac, through the fetal period and for a variable time during the first three postnatal weeks. Thereafter, no expression of any of the gamma-globin genes was seen in adult erythroid tissues. Transcription from the normal G gamma and HPFH A gamma genes in the first construct paralleled each other in developmental timing, with a proportionate excess of A gamma more evident in later gestation. G gamma and A gamma mRNA transcripts from the normal G gamma + 4 bp deletional A gamma construct were unable to be distinguished because of a 3' G gamma-like conversion in the deletional A gamma gene. Combined gamma-globin expression from the two genes in this second construct was detectable until just after birth, as seen with the individual genes in the first construct.(ABSTRACT TRUNCATED AT 250 WORDS)