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BMC Med Genet. 2017 Aug 29;18(1):93. doi: 10.1186/s12881-017-0450-3.

An Aγ-globin G->A gene polymorphism associated with β039 thalassemia globin gene and high fetal hemoglobin production.

Author information

1
Department of Life Sciences and Biotechnology, Ferrara University, Via Fossato di Mortara 74, 44121, Ferrara, Italy.
2
Biotechnology Center, Ferrara University, Ferrara, Italy.
3
Department of Medical Sciences - Pediatry, Ferrara University, Ferrara, Italy.
4
Department of Transfusional Medicine - ULSS 18, Rovigo, Italy.
5
Department of Life Sciences and Biotechnology, Ferrara University, Via Fossato di Mortara 74, 44121, Ferrara, Italy. gam@unife.it.
6
Biotechnology Center, Ferrara University, Ferrara, Italy. gam@unife.it.

Abstract

BACKGROUND:

Increase of the expression of γ-globin gene and high production of fetal hemoglobin (HbF) in β-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify β-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea).

METHODS:

Aγ-globin gene sequencing was performed on genomic DNA isolated from a total of 75 β-thalassemia patients, including 31 β039/β039, 33 β039/β+IVSI-110, 9 β+IVSI-110/β+IVSI-110, one β0IVSI-1/β+IVSI-6 and one β039/β+IVSI-6.

RESULTS:

The results show that the rs368698783 polymorphism is present in β-thalassemia patients in the 5'UTR sequence (+25) of the Aγ-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This Aγ(+25 G->A) polymorphism is associated with the Gγ-globin-XmnI polymorphism and both are linked with the β039-globin gene, but not with the β+IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the Aγ(+25 G->A) and Gγ-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from β039/β039 thalassemia patients.

CONCLUSIONS:

As a potential explanation of our findings, we hypothesize that in β-thalassemia the Gγ-globin-XmnI/Aγ-globin-(G->A) genotype is frequently under genetic linkage with β0-thalassemia mutations, but not with the β+-thalassemia mutation here studied (i.e. β+IVSI-110) and that this genetic combination has been selected within the population of β0-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the Aγ-globin gene associated in β039 thalassemia patients with high HbF in erythroid precursor cells.

KEYWORDS:

Aγ-globin gene polymorphism; Fetal hemoglobin; LYAR; β-thalassemia

PMID:
28851297
PMCID:
PMC5575872
DOI:
10.1186/s12881-017-0450-3
[Indexed for MEDLINE]
Free PMC Article

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