Skip to main content
SpringerLink
Log in

Association of alpha hemoglobin–stabilizing protein (AHSP) gene mutation and disease severity among HbE—beta thalassemia patients

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

In this study, we aimed to investigate the pattern and association of genetic mutations occurring within the alpha hemoglobin–stabilizing protein (AHSP) gene among HbE beta thalassemia patients with varying phenotypic expressions. Fifty-four diagnosed cases of HbE beta thalassemia (transfusion dependent and independent) were included in the study. Among them, 38 patients with similar genotypes (IVS 1–5, alpha gene deletion and triplication, Xmn polymorphism) were selected for further analysis. AHSP gene sequencing was done for these 38 samples to study associated mutations in AHSP gene. HbE beta thalassemia patients with similar genotypes but different phenotypic expressions were found to have mutations in the AHSP gene. There were five mutations found most prevalent among the samples analyzed for AHSP gene sequencing. Among these, two mutations were from intron 1 region of AHSP and three mutations were found in exon 3. The most prevalent mutation was found at the Oct binding site at intron 1 of AHSP. The mutations in exon 3 were more prevalent among the TDT groups. A mutation in exon 3 changing the amino acid (33rd) from serine to phenylalanine was found to be associated with only TDT group. This study documents that among the HbE beta thalassemia patients with varying severity, an exon mutation in AHSP is significantly prevalent only among the TDT group. Further understanding of the mechanism will shed light upon the impact of AHSP in modifying the disease severity in thalassemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

NTDT:

Non-transfusion-dependent thalassemia

TDT:

Transfusion-dependent thalassemia

HPFH:

Hereditary persistence of fetal hemoglobin

AHSP:

Alpha hemoglobin–stabilizing protein

RBC:

Red blood cells

Hb:

Hemoglobin

HbF:

Fetal hemoglobin

References

  1. Higgs DR (1993) The thalassaemia syndromes. Q J Med 86(9):559–564

    CAS  PubMed  Google Scholar 

  2. Kihm AJ, Kong Y, Hong W, Russell JE, Rouda S, Adachi K, Simon MC, Blobel GA, Weiss MJ (2002) An abundant erythroid protein that stabilizes free alpha-haemoglobin. Nature 417(6890):758–763

    Article  CAS  PubMed  Google Scholar 

  3. Feng L, Gell DA, Zhou S, Gu L, Kong Y, Li J, Hu M, Yan N, Lee C, Rich AM, Armstrong RS, Lay PA, Gow AJ, Weiss MJ, Mackay JP, Shi Y (2004) Molecular mechanism of AHSP-mediated stabilization of alpha-hemoglobin. Cell 119(5):629–640

    Article  CAS  PubMed  Google Scholar 

  4. Kong Y, Zhou S, Kihm AJ, Katein AM, Yu X, Gell DA, Mackay JP, Adachi K, Foster-Brown L, Louden CS, Gow AJ, Weiss MJ (2004) Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia. J Clin Invest 114(10):1457–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lai MI, Jiang J, Silver N, Best S, Menzel S, Mijovic A, Colella S, Ragoussis J, Garner C, Weiss MJ, Thein SL (2006) Alpha-haemoglobin stabilising protein is a quantitative trait gene that modifies the phenotype of beta-thalassaemia. Br J Haematol 133(6):675–682

    Article  CAS  PubMed  Google Scholar 

  6. Santiveri CM, Perez-Canadillas JM, Vadivelu MK et al (2004) NMR structure of the alpha-hemoglobin stabilizing protein: insights into conformational heterogeneity and binding. J Biol Chem 279(33):34963–34970

    Article  CAS  PubMed  Google Scholar 

  7. Viprakasit V, Tanphaichitr VS, Chinchang W, Sangkla P, Weiss MJ, Higgs DR (2004) Evaluation of alpha hemoglobin stabilizing protein (AHSP) as a genetic modifier in patients with beta thalassemia. Blood 103(9):3296–3299

    Article  CAS  PubMed  Google Scholar 

  8. Luzzatto L, Notaro R (2002) Haemoglobin’s chaperone. Nature 417(6890):703–705

    Article  CAS  PubMed  Google Scholar 

  9. dos Santos CO, Duarte AS, Saad ST, Costa FF (2004) Expression of alpha-hemoglobin stabilizing protein gene during human erythropoiesis. Exp Hematol 32(2):157–162

    Article  CAS  PubMed  Google Scholar 

  10. dos Santos CO, Zhou S, Secolin R, Wang X, Cunha AF, Higgs DR, Kwiatkowski JL, Thein SL, Gallagher PG, Costa FF, Weiss MJ (2008) Population analysis of the alpha hemoglobin stabilizing protein (AHSP) gene identifies sequence variants that alter expression and function. Am J Hematol 83(2):103–108

    Article  CAS  PubMed  Google Scholar 

  11. Gallagher PG, Liem RI, Wong E, Weiss MJ, Bodine DM (2005) GATA-1 and Oct-1 are required for expression of the human alpha-hemoglobin-stabilizing protein gene. J Biol Chem 280(47):39016–39023

    Article  CAS  PubMed  Google Scholar 

  12. Lettre G (2012) The search for genetic modifiers of disease severity in the β-hemoglobinopathies. Cold Spring Harbor perspectives in medicine 2(10):a015032

  13. Ranjbaran R, Okhovat MA, Mobarhanfard A et al (2014) Relationship between AHSP gene expression, beta/alpha globin mRNA ratio, and clinical severity of the beta-thalassemia patients. Ann Clin Lab Sci 44(2):189–193

    CAS  PubMed  Google Scholar 

  14. Wang Z, Yu W, Li Y, Shang X, Zhang X, Xiong F, Xu X (2010) Analysis of alpha-hemoglobin-stabilizing protein (AHSP) gene as a genetic modifier to the phenotype of beta-thalassemia in Southern China. Blood Cells Mol Dis 45(2):128–132

    Article  CAS  PubMed  Google Scholar 

  15. Bhagat S, Patra PK, Thakur AS (2012) Association between XmnI polymorphism and HbF level in sickle cell disease patients from Chhattisgarh. Int J Biomed Sci 8(1):36–39

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu YT, Old JM, Miles K, Fisher CA, Weatherall DJ, Clegg JB (2000) Rapid detection of alpha-thalassaemia deletions and alpha-globin gene triplication by multiplex polymerase chain reactions. Br J Haematol 108(2):295–299

    Article  CAS  PubMed  Google Scholar 

  17. Wang W, Ma ES, Chan AY, Prior J, Erber WN, Chan LC, Chui DH, Chong SS (2003) Single-tube multiplex-PCR screen for anti-3.7 and anti-4.2 alpha-globin gene triplications. Clin Chem 49(10):1679–1682

    Article  CAS  PubMed  Google Scholar 

  18. Gell DA, Feng L, Zhou S, Jeffrey PD, Bendak K, Gow A, Weiss MJ, Shi Y, Mackay JP (2009) A cis-proline in alpha-hemoglobin stabilizing protein directs the structural reorganization of alpha-hemoglobin. J Biol Chem 284(43):29462–29469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical College, Institute of Hematology and Transfusion Medicine, Kolkata, India

    Rudra Ray, Sunistha Bhattacharjee, Ankita Biswas, Aiman Shahab & Sujana Biswas

  2. Medical College, Institute of Hematology and Transfusion Medicine, Kolkata, India

    Siddhesh Arun Kalantri & Maitreyee Bhattacharyya

Authors
  1. Rudra Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Siddhesh Arun Kalantri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sunistha Bhattacharjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ankita Biswas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aiman Shahab
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sujana Biswas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maitreyee Bhattacharyya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maitreyee Bhattacharyya.

Ethics declarations

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed consent was obtained from all patients for being included in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Financial relationship

There is no financial relationship involved with the organization sponsored the research.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ray, R., Kalantri, S.A., Bhattacharjee, S. et al. Association of alpha hemoglobin–stabilizing protein (AHSP) gene mutation and disease severity among HbE—beta thalassemia patients. Ann Hematol 98, 1827–1834 (2019). https://doi.org/10.1007/s00277-019-03722-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-019-03722-x

Keywords

Search

Navigation