Analysis of the mechanism of action of non-deletion hereditary persistenceof fetal hemoglobin mutants in transgenic mice

Citation
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
Citations number
31
Categorie Soggetti
Molecular Biology & Genetics
Journal title
EMBO JOURNAL
ISSN journal
02614189 → ACNP
Volume
20
Issue
1-2
Year of publication
2001
Pages
157 - 164
Database
ISI
SICI code
0261-4189(20010115)20:1-2<157:AOTMOA>2.0.ZU;2-G
Abstract
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.