Molecular Diagnosis & Therapy

, Volume 20, Issue 2, pp 161–173

Structural and Functional Insights on an Uncharacterized Aγ-Globin-Gene Polymorphism Present in Four β0-Thalassemia Families with High Fetal Hemoglobin Levels

  • Nicoletta Bianchi
  • Lucia Carmela Cosenza
  • Ilaria Lampronti
  • Alessia Finotti
  • Giulia Breveglieri
  • Cristina Zuccato
  • Enrica Fabbri
  • Giovanni Marzaro
  • Adriana Chilin
  • Gioia De Angelis
  • Monica Borgatti
  • Cristiano Gallucci
  • Cecilia Alfieri
  • Michela Ribersani
  • Antonella Isgrò
  • Marco Marziali
  • Javid Gaziev
  • Aldo Morrone
  • Pietro Sodani
  • Guido Lucarelli
  • Roberto Gambari
  • Katia Paciaroni
Original Research Article

DOI: 10.1007/s40291-016-0187-2

Cite this article as:
Bianchi, N., Cosenza, L.C., Lampronti, I. et al. Mol Diagn Ther (2016) 20: 161. doi:10.1007/s40291-016-0187-2
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Abstract

Introduction

Several DNA polymorphisms have been associated with high production of fetal hemoglobin (HbF), although the molecular basis is not completely understood. In order to identify and characterize novel HbF-associated elements, we focused on five probands and their four families (from Egypt, Iraq and Iran) with thalassemia major (either β0-IVSII-1 or β0-IVSI-1) and unusual HbF elevation (>98 %), congenital or acquired after rejection of bone marrow transplantation, suggesting an anticipated favorable genetic background to high HbF expression.

Methods

Patient recruitment, genomic DNA sequencing, western blotting, electrophoretic mobility shift assays, surface plasmon resonance (SPR) biospecific interaction analysis, bioinformatics analyses based on docking experiments.

Results

A polymorphism of the Aγ-globin gene is here studied in four families with β0-thalassemia (β0-IVSII-1 and β0-IVSI-1) and expressing unusual high HbF levels, congenital or acquired after rejection of bone marrow transplantation. This (G→A) polymorphism is present at position +25 of the Aγ-globin genes, corresponding to a 5′-UTR region of the Aγ-globin mRNA and, when present, is physically linked in chromosomes 11 of all the familiar members studied to the XmnI polymorphism and to the β0-thalassemia mutations. The region corresponding to the +25(G→A) polymorphism of the Aγ-globin gene belongs to a sequence recognized by DNA-binding protein complexes, including LYAR (Ly-1 antibody reactive clone), a zinc-finger transcription factor previously proposed to be involved in down-regulation of the expression of γ-globin genes in erythroid cells.

Conclusion

We found a novel polymorphism of the Aγ-globin gene in four families with β0-thalassemia and high levels of HbF expression. Additionally, we report evidence suggesting that the Aγ-globin gene +25(G→A) polymorphism decreases the efficiency of the interaction between this sequence and specific DNA binding protein complexes.

Supplementary material

40291_2016_187_MOESM1_ESM.docx (1.4 mb)
Supplementary material 1 (DOCX 1384 kb)

Funding information

Funder NameGrant NumberFunding Note
Fondazione Telethon (IT)
  • GGP10124
Seventh Framework Programme (BE)
  • THALAMOSS-306201-FP7
Ministero della Salute (IT)
  • 098/GR-2009-1596647

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Nicoletta Bianchi
    • 1
  • Lucia Carmela Cosenza
    • 1
  • Ilaria Lampronti
    • 1
  • Alessia Finotti
    • 1
  • Giulia Breveglieri
    • 1
  • Cristina Zuccato
    • 1
  • Enrica Fabbri
    • 1
  • Giovanni Marzaro
    • 2
  • Adriana Chilin
    • 2
  • Gioia De Angelis
    • 3
  • Monica Borgatti
    • 1
  • Cristiano Gallucci
    • 3
  • Cecilia Alfieri
    • 3
  • Michela Ribersani
    • 3
  • Antonella Isgrò
    • 3
  • Marco Marziali
    • 3
  • Javid Gaziev
    • 3
  • Aldo Morrone
    • 3
  • Pietro Sodani
    • 3
  • Guido Lucarelli
    • 3
  • Roberto Gambari
    • 1
    • 4
  • Katia Paciaroni
    • 3
  1. 1.Department of Life Sciences and BiotechnologyFerrara UniversityFerraraItaly
  2. 2.Department of Pharmaceutical and Pharmacological SciencesUniversity of PadovaPaduaItaly
  3. 3.International Centre for Transplantation in Thalassemia and Sickle Cell AnaemiaMediterranean Institute of Haematology, Policlinic of “Tor Vergata” UniversityRomeItaly
  4. 4.Biotechnology CenterFerrara UniversityFerraraItaly

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