Τίτλος:
The Corfu delta beta thalassemia deletion disrupts gamma-globin gene
silencing and reveals post-transcriptional regulation of HbF expression
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The 7.2 kilobase (kb) Corfu deltabeta thalassemia mutation is the
smallest known deletion encompassing a region upstream of the human
delta gene that has been suggested to account for the vastly different
phenotypes in hereditary persistence of fetal hemoglobin (HPFH) versus
beta thalassemia. Fetal hemoglobin (HbF) expression in Corfu
heterozygotes and homozygotes is paradoxically dissimilar, suggesting
conflicting theories as to the function of the region on globin gene
regulation. Here, we measure gamma- and beta-globin gene transcription,
steady-state mRNA, and hemoglobin expression levels in primary erythroid
cells cultured from several patients with Corfu deltabeta thalassemia.
We show through RNA fluorescence in situ hybridization that the Corfu
deletion results in high-level transcription of the fetal gamma genes in
cis with a concomitant reduction in transcription of the downstream beta
gene. Surprisingly, we find that elevated gamma gene transcription does
not always result in a corresponding accumulation of gamma mRNA or fetal
hemoglobin, indicating a post-transcriptional regulation of gamma gene
expression. The data suggest that efficient gamma mRNA accumulation and
HbF expression are blocked until beta mRNA levels fall below a critical
threshold. These results explain the Corfu paradox and show that the
deleted region harbors a critical element that functions in the
developmentally regulated transcription of the beta-globin genes. (C)
2005 by The American Society of Hematology
Συγγραφείς:
Chakalova, L
Osborne, CS
Dai, YF
Goyenechea, B and
Metaxotou-Mavromati, A
Kattamis, A
Kattamis, C
Fraser, P
Περιοδικό:
Blood advances
Εκδότης:
AMER SOC HEMATOLOGY
DOI:
10.1182/blood-2003-11-4069
