Ql. Li et al., Analysis of the mechanism of action of non-deletion hereditary persistenceof fetal hemoglobin mutants in transgenic mice, EMBO J, 20(1-2), 2001, pp. 157-164
Transgenic mice carrying an (A)gamma gene construct containing a -382 5' tr
uncation of the (A)gamma gene promoter have a phenotype of hereditary persi
stence of fetal hemoglobin (HPFH) but, when the CACCC box of the -382(A)gam
ma promoter is deleted, there is no gamma gene expression in the adult mice
. We used this system to investigate the mechanism whereby human HPFH mutat
ions result in gamma gene expression in the adult. Introduction of the -198
T-->C HPFH mutation into the CACCC-less (A)gamma gene construct re-establi
shed the HPFH phenotype, indicating that this mutation increases promoter s
trength, most probably by establishing a novel CACCC box sequence in the -1
98(A)gamma region. The HPFH phenotype was also re-established when the -117
C-->T HPFH mutation was introduced into a -141(A)gamma promoter with a des
troyed CACCC box, indicating that this mutation increases gamma promoter st
rength in the absence of the CACCC motif, The T-->A -175 HPFH mutation fail
ed to re-establish the HPFH phenotype when the CACCC box was deleted, indic
ating that gamma gene expression in this mutation is CACCC box dependent. T
hese results provide the first in vivo experimental evidence in support of
mechanistic heterogeneity of the non-deletion HPFH mutants.