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C>A substitution in NT 46 of the 3’ UTR region (the α complex protected region) of the alpha-1 globin gene: a non-deletional mutation or polymorphism?
  1. Paloma Ropero1,
  2. Fernando Ataúlfo González1,
  3. Jorge M Nieto1,
  4. Ana Villegas1,
  5. Julian Sevilla2,
  6. Germán Pérez3,
  7. José María Alonso4,
  8. Valle Recasens5,
  9. Mariola Abio6,
  10. Jose Manuel Vagace7,
  11. Raul Jesus Vanegas8,
  12. Beatriz González Fernández1,
  13. Rafael Martínez1
  1. 1 Hematology, Hospital Clínico San Carlos, Madrid, Spain
  2. 2 Hematology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
  3. 3 Hematology, Hospital Sierrallana y Tres Mares, Torrelavega, Spain
  4. 4 Hematology, Complejo Asistencial de Palencia, Palencia, Spain
  5. 5 Hematology, Hospital Universitario Miguel Servet, Zaragoza, Spain
  6. 6 Hematology, Hospital Virgen de la Salud, Toledo, Spain
  7. 7 Hematology, Hospital Materno Infantil, Badajoz, Spain
  8. 8 Hematology, Hospital General de Ciudad Real, Ciudad Real, Spain
  1. Correspondence to Dr Paloma Ropero, Hospital Clínico San Carlos, Madrid 28040, Spain; paloma.ropero{at}


Aims Untranslated regions (UTRs) play an important role in post-transcriptional regulation of gene expression, including by modulating messenger RNA (mRNA) transport out of the nucleus, translation efficiency, subcellular localisation and stability. Any mutation in this region could alter the stability of mRNA and thereby affect protein synthesis. We analysed if a mutation located in the α complex protected region of the α1 globin gene could cause non-deletional α-thalassaemia by affecting post-transcriptional stability (mRNA stability).

Methods A total of 14 patients without anaemia, normal or slight microcytosis and hypochromia (medium concentration haemoglobin [MCH] <27 pg) were studied. Haemoglobin subtypes were screened using capillary zone electrophoresis and ion-exchange high-performance liquid chromatography (VARIANT II β-Thalassaemia Short Program). The most common α-globin mutations were identified by multiplex PCR (Alpha-Globin StripAssay kit) and the molecular characterisation by automatic sequencing of alpha globin genes.

Results All of them shown a novel transversion mutation in nt 778 (C>A), which is located in the 3' UTR in the α complex protected region [HBA1: c.*+46C>A].

Conclusions This mutation is in the αRNAmin binding site, so a single nucleotide substitution in this region can decrease mRNA stability by potentially compromising the binding of α-complex protein to αRNAmin, favouring the decay of α-globin mRNA via erythroid cell-enriched endoribonuclease cleavage. In this case, it is a non-deletional α-thalassaemia. However, in silico and empirical studies predicted that it could be a silent polymorphism. Functional studies should be carried out to confirm whether it is a pathological mutation or a silent polymorphism.

  • non-deletional alpha-thalassemia
  • mRNA stability
  • mutations in 3' UTR alpha globin gene
  • polymorphism

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  • Handling editor Mary Frances McMullin.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Ethics Committee of the Hospital Clínico San Carlos (Madrid, Spain).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplementary information.

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