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

AUTOR(ES)

Li, Qiliang

FONTE

Oxford University Press

RESUMO

Transgenic mice carrying an Aγ gene construct containing a –382 5′ truncation of the Aγ gene promoter have a phenotype of hereditary persistence of fetal hemoglobin (HPFH) but, when the CACCC box of the –382Aγ promoter is deleted, there is no γ gene expression in the adult mice. We used this system to investigate the mechanism whereby human HPFH mutations result in γ gene expression in the adult. Introduction of the –198 T→C HPFH mutation into the CACCC-less Aγ gene construct re-established the HPFH phenotype, indicating that this mutation increases promoter strength, most probably by establishing a novel CACCC box sequence in the –198Aγ region. The HPFH phenotype was also re-established when the –117 C→T HPFH mutation was introduced into a –141Aγ promoter with a destroyed CACCC box, indicating that this mutation increases γ promoter strength in the absence of the CACCC motif. The T→A –175 HPFH mutation failed to re-establish the HPFH phenotype when the CACCC box was deleted, indicating that γ gene expression in this mutation is CACCC box dependent. These results provide the first in vivo experimental evidence in support of mechanistic heterogeneity of the non-deletion HPFH mutants.

Documentos Relacionados

• Non-deletion haemoglobin H disease in Papua New Guinea.
• Expression of the Affected Aγ Globin Gene Associated with Greek Nondeletion Hereditary Persistence of Fetal Hemoglobin
• Expression of the affected A gamma globin gene associated with Greek nondeletion hereditary persistence of fetal hemoglobin.
• A fetal globin gene mutation in A gamma nondeletion hereditary persistence of fetal hemoglobin increases promoter strength in a nonerythroid cell.
• The non-deletion alpha thalassaemia/mental retardation syndrome: further support for X linkage.