Molecular Analysis of γ-Globin Promoters, HS-111 and 3′HS1, in β-thalassemia Intermedia Patients Associated with High Levels of Hb F

Abstract

The nucleotide (nt) variations in the promoter region of the gamma-globin genes, HS-111 and 3'HS1 regions, were studied in Iranian patients with beta-thalassemia intermedia (beta-TI), beta-thalassemia major (beta-TM) and healthy individuals. Of the five nt variations at the 5' end of the (A)gamma-globin gene, -369 (C>G), -611 (-T) and -603/604 (GA>AG) were found in all samples, whereas -588 (A>G) and -AAGC at -222 to -225 were found at different frequencies in the studied groups. Therefore, the -369, -611 and -603/604 variations were considered common mutations in this population, and the difference with respect to the -AAGC deletion was not significant. However, the A allele of the -588 variation and [+] allele of the XmnI polymorphism were more frequent in beta-TI patients, especially those who had the IVS-II-1(G>A)/IVS-II-1(G>A) genotype. The + allele of XmnI also had complete correlation with the A allele of -588 variation. The HS-111 (-21 A) variation also showed association with beta-TI patients who had high levels of Hb F. Bearing in mind that the -588 variation lies within the postulated adult-specific silencer region and that the majority of beta-TI patients had allele A, then it can be envisaged that this allele could have a role in altering the repressor function at this region. Therefore, the A allele of -588, [+] allele of XmnI and HS-111 (-21 A) variation are useful genetic markers to differentiate between beta-TM and beta-TI patients. However, these nt changes alone may not be the only elements raising the level of Hb F, other regulatory and modifying factors also play a role in Hb F production.

Genetic Epidemiology, Hematological and Clinical Features of Hemoglobinopathies in Iran

“…Further, the main molecular basis of the β -thalassemia intermedia phenotype in Iranian cases was determined to be the coinheritance of a positive Xmn I polymorphism with β -globin mutations resulted in increase Hb F production, coinheritance of α -globin defects, and mild presentation of β -globin mutations [59]. Also, HS-111 and 3′HS1 in the promoter region of γ -globin gene in β -thalassemia intermedia patients were associated with high level of Hb F [60]. …”

HBG2 and HBG1 Nucleotide Substitutions and Hbf Production in Thalassemia Patients

“…However, HbF may be slightly or significantly elevated during adulthood. A high level of HbF is mainly due to pathological conditions such as β-thalassemia major, δβ-thalassemia, (as γ globin chains compensate for the lack of functional β-globin chains) erythropoietic stress and bone marrow malignancies, or nonpathological conditions, known as HPFH, such as large deletions within the β-globin gene cluster (deletional HPFH), promoter variants of γ globin genes (non deletional HPFH) or pregnancy [2][3][4]. While persistence of increased HbF production has no clinical consequences in healthy individuals, HbF is one of the most common and major modifiers of disease severity in individuals with β-thalassemia [5][6][7][8].…”

Genetic research and clinical analysis of β‐globin gene cluster deletions in the Chinese population of Fujian province: A 14‐year single‐center experience

“…Moreover, KLF1 mutations were selectively reported in the presence of β‐thalassemia to increase the production of HbF 17 . Patients with β‐thalassemia showed an increased level of HbF, which may be the result of the polymorphism of Xmnl and p. Ser102Pro (c.304T> C) in the Krüppel‐like factor (1 KLF1) gene, or because of the number of α‐gene deletions 18–21 . In the 29 cases with common α‐thalassemia, 26 cases were confirmed with ‐α4.2/αα and screened by capillary electrophoresis, which was suspected to be compound with HbQ‐Thailand and confirmed by DNA sequencing of the α genes (data not shown) 22,23 .…”