Upstream promoter mutation associated with a modest elevation of fetal hemoglobin expression in human adults

Abstract

In hereditary persistence of fetal hemoglobin, Hb F (alpha 2 gamma 2) is elevated after birth. Screening of sickle cell patients has revealed a family with elevated Hb F and high A gamma values. The propositus was a sickle cell patient with approximately 25% Hb F and 68.4% A gamma. He was heterozygous for the Benin (#19) and Mor beta S haplotypes. Five AS relatives with the Mor haplotype had 2.5% +/- 0.9% fetal hemoglobin and 92.8% +/- 2.8% A gamma, whereas two with the Benin haplotype had normal fetal hemoglobin (0.5%). The Mor haplotype is thus associated with the elevated Hb F in this family. The 13-kilobase (kb) Bg/II fragment containing the G gamma and A gamma genes of the Mor haplotype was cloned, and the G gamma and A gamma promoters sequenced from -383 to beyond the Cap sites. The Mor G gamma gene was normal, but the A gamma gene had a unique C----T mutation at -202. A different mutation at -202 of G gamma (C----G) was previously detected by other researchers in association with considerably higher Hb F in AS cases (15% to 25%). These data suggest either that -202 mutations affect the G gamma and A gamma promoters differently or that different nucleotide substitutions at -202 have divergent effects. Alternatively, additional unknown mutations could cause the differences in gene expression.

Fetal hemoglobin synthesis in sickle cell anemia: Some molecular considerations

“…Any difference between the G , and A, chains in their ability to form the a2psy hybrid could explain the variable response to hydroxyurea observed among the SS patient population [8]. Interestingly enough, a C+T substitution has been identified at position -202 to the cap site of *y globin gene of the chromosome with the Mor haplotype [37]. The -202 Gy (C-G) mutation, however, has not been found to be associated with the symptomatic SS patients with high fetal hemoglobin [38].…”

Analysis of the mechanism of action of the Brazilian type (Aγ−195 C → G) of hereditary persistence of fetal hemoglobin

“…Non-deletional forms of HPFH are characterized by single-base mutations in the promoter region (most of them between )114 and )202 from the cap site) of either the G c or A c-globin gene, resulting in an increase of HbF ranging from 3 to 20% in heterozygotes. Many point mutations in this region have been described, including the Greek type ( A c)117 G fi A) (1), Black type ( A c)175 T fi A) (2), Brazilian type ( A c)195 C fi G) (3), Chinese type ( A c)196 C fi T) (4), British type ( A c)198 T fi C) (5) and Black type ( A c)202 C fi T) (6) HPFHs. It is believed that this mutation may modify the binding of trans-acting factors to critical regions of the promoters, resulting in their continuous expression during adult life (1, 5, 7-10).…”

Μελέτη Και Αξιοποίηση Των Λειτουργικών Ιδιοτήτων Των Μεσεγχυματικών Βλαστικών Κυττάρων Διαφόρων Πηγών

“…Ο KLF1 φαίνεται να καταστέλλει έµµεσα την HbF προσφέροντας ανταγωνιστικό πλεονέκτηµα στην έκφραση του β-γονιδίου (Wijgerde et al, 1996; (Li et al, 2001), είτε αποτρέποντας την πρόσδεση ανασταλτικών παραγόντων είτε δηµιουργώντας νέες θέσεις πρόσδεσης παραγόντων που αυξάνουν την έκφραση του γονιδίου (Mantovani et al, 1988;Martin et al, 1989) . Οι πιο αξιοσηµείωτες από αυτές είναι η µετάλλαξη στη θέση -202 και στη θέση -175 τόσο του G γ όσο και του Α γ γονιδίου, καθώς και η µετάλλαξη στη θέση -198 του Α γ γονιδίου (Gilman et al, 1988;Nicolis et al, 1989;Ronchi et al, 1989). Η µετάλλαξη που έχει µελετηθεί καλύτερα είναι η αντικατάσταση της γουανίνης στο σηµείο -117 του Α γ υποκινητή από αδενίνη (Collins et al, 1987) (Πίνακας 1).…”