Human Gγ and Aγ globin gene constructs containing the 3′ Aγ enhancer show persistent fetal expression in transgenic mice

Abstract

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)