Skip to main content
SpringerLink
Log in

Genetics of Iranian Alpha-Thalassemia Patients: A Comprehensive Original Study

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

Alpha thalassemia is the most prevalent monogenic gene disorder in the world, especially in Mediterranean countries. In the current hematological phenotype of patients with different genotypes, the effects of missense mutations on the protein function and also stability were evaluated in a large cohort study. A total of 1,560 subjects were enrolled in the study and divided into two groups: 259 normal subjects; and 1301 alpha-thalassemia carriers. Genomic DNA was extracted and analyzed using ARMS PCR, Multiplex Gap, and direct sequencing. The effects of single nucleotide change on the protein function and stability were predicted by freely available databases of human polymorphisms. Sixty-three different genotypes were seen in the patients. The more prevalent was heterozygote form of −α3.7 (41.4%) followed by −α3.7 homozygote (11.6%) and −MED (3.8%). The significant differences were seen in mean hemoglobin level [F = 20.5, p < 0.001] between the Alpha-globin genotypes, when adjusted for gender. Moreover, 28 different mutations were found in our study. A significant relationship was seen between ethnicity and the alpha-globin mutation frequency χ2 (df;8) = 38.36, p < 0.0001). Different genotypes could display as different phenotypes. The mutation frequency distributions in our region are different from those of other parts of Iran. Significant differences are seen in the spectrum of mutation frequency among various ethnicities. Finally, some missense mutations might not have considerable effect on the proteins, and they could be neutral mutations.

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

Similar content being viewed by others

References

  • Akhavan-Niaki H, Kamangari RY, Banihashemi A, Oskooei VK, Azizi M, Tamaddoni A et al (2012) Hematologic features of alpha thalassemia carriers. Int J Mol Cell Med 1(3):162

    PubMed  PubMed Central  Google Scholar 

  • Alibakhshi R, Mehrabi M, Omidniakan L, Shafieenia S (2015) The spectrum of α-thalassemia mutations in Kermanshah Province, West Iran. Hemoglobin 39(6):403–406

    Article  CAS  Google Scholar 

  • Bayat N, Farashi S, Hafezi-Nejad N, Faramarzi N, Ashki M, Vakili S et al (2013) Novel mutations responsible for α-thalassemia in Iranian families. Hemoglobin 37(2):148–159

    CAS  PubMed  Google Scholar 

  • Bendl J, Stourac J, Salanda O, Pavelka A, Wieben ED, Zendulka J et al (2014) PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput Biol 10(1):e1003440

    Article  Google Scholar 

  • Capriotti E, Fariselli P, Casadio R (2005) I-Mutant2. 0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 33(suppl_2):W306–W310

    Article  CAS  Google Scholar 

  • Chui DH, Fucharoen S, Chan V (2003) Hemoglobin H disease: not necessarily a benign disorder. Blood 101(3):791–800

    Article  CAS  Google Scholar 

  • Denic S, Agarwal MM, Al Dabbagh B, El Essa A, Takala M, Showqi S et al (2013) Hemoglobin A 2 lowered by iron deficiency and α-thalassemia: should screening recommendation for β-thalassemia change? ISRN Hematol. 2013:858294

    Article  Google Scholar 

  • Eng B, Patterson M, Walker L, Chui DH, Waye JS (2001) Detection of severe nondeletional α-thalassemia mutations using a single-tube multiplex ARMS assay. Genetic Test 5(4):327–329

    Article  CAS  Google Scholar 

  • Farashi S, Garous NF, Ashki M, Vakili S, Zeinali F, Imanian H et al (2015) Homozygosity for the AATA AA>AATA—polyadenylation site mutation on the α 2-globin gene causing transfusion-dependent Hb H disease in an Iranian patient: a case report. Hemoglobin 39(5):355–358

    CAS  PubMed  Google Scholar 

  • Farra C, Daher R, Badra R, el Rafei R, Bejjany R, Charafeddine L et al (2015) Incidence of alpha-globin gene defect in the lebanese population: a pilot study. BioMed Res Int 2015:517679

    Article  Google Scholar 

  • Fei Y-J, Öner R, Bözkurt G, Gu L-H, Altay Ç, Gurgey A et al (1992) Hb H disease caused by a homozygosity for the AATAAA → AATAAG mutation in the polyadenylation site of the α2-globin gene: hematological observations. Acta Haematol 88(2–3):82–85

    Article  CAS  Google Scholar 

  • Galanello R, Cao A (2011) Alpha-thalassemia. Genet Med 13(2):83–88

    Article  CAS  Google Scholar 

  • Hafezi-Nejad N, Khosravi M, Bayat N, Kariminejad A, Hadavi V, Oberkanins C et al (2014) Characterizing a cohort of α-thalassemia couples collected during screening for hemoglobinopathies: 14 years of an iranian experience. Hemoglobin 38(3):153–157

    Article  CAS  Google Scholar 

  • Harteveld CL, Higgs DR (2010) α-thalassaemia. Orphanet J Rare Dis 5(1):13

    Article  Google Scholar 

  • Harteveld C, Losekoot M, Haak H, Heister J, Giordano P, Bernini L (1994) A novel polyadenylation signal mutation in the α2-globin gene causing α thalassaemia. Br J Haematol 87(1):139–143

    Article  CAS  Google Scholar 

  • Haywood A, Dreau H, Timbs A, Schuh A, Old J, Henderson S (2010) Screening for clinically significant non-deletional alpha thalassaemia mutations by pyrosequencing. Ann Hematol 89(12):1215–1221

    Article  CAS  Google Scholar 

  • Irani AD, Cheraghi Z, Bitaraf S, Cheraghi P, Safiri S (2015) Prevalence of alpha and beta-thalassemia mutations among carriers of thalassemia in Shadegan City, Southwest of Iran. Zahedan J Res Med Sci. https://doi.org/10.17795/zjms1032

    Article  Google Scholar 

  • Jalali H, Mahdavi MR, Roshan P, Kosaryan M, Karami H, Mahdavi M (2014) Alpha thalassemia gene mutations in neonates from Mazandaran, Iran, 2012. Hematology. 19(4):192–195

    Article  CAS  Google Scholar 

  • Karamzade A, Mirzapour H, Hoseinzade M, Asadi S, Gholamrezapour T, Tavakoli P et al (2014) α-Globin gene mutations in Isfahan Province, Iran. Hemoglobin. 38(3):161–164

    Article  CAS  Google Scholar 

  • Khosravi A, Jalali-Far M, Saki N, Hosseini H, Galehdari H, Kiani-Ghalesardi O et al (2016) Evaluation of α-globin gene mutations among different ethnic groups in Khuzestan Province, Southwest Iran. Hemoglobin. 40(2):113–117

    Article  CAS  Google Scholar 

  • Kountouris P, Kousiappa I, Papasavva T, Christopoulos G, Pavlou E, Petrou M et al (2016) The molecular spectrum and distribution of haemoglobinopathies in Cyprus: a 20-year retrospective study. Sci Rep 6:26371

    Article  CAS  Google Scholar 

  • Liebhaber SA, Cash FE, Main DM (1985) Compensatory increase in alpha 1-globin gene expression in individuals heterozygous for the alpha-thalassemia-2 deletion. J Clin Investig 76(3):1057

    Article  CAS  Google Scholar 

  • Liu Y, Old J, Miles K, Fisher C, Weatherall D, Clegg J (2000) Rapid detection of a-thalassaemia deletions and a-globin gene triplication by multiplex polymerase chain reactions. Br J Haematol 108(2):295–299

    Article  CAS  Google Scholar 

  • Michelson A, Orkin S (1983) Boundaries of gene conversion within the duplicated human alpha-globin genes. Concerted evolution by segmental recombination. J Biol Chem 258(24):15245–15254

    CAS  PubMed  Google Scholar 

  • Miri M, Tabrizi Namini M, Hadipour Dehshal M, Sadeghian Varnosfaderani F, Ahmadvand A, Yousefi Darestani S et al (2013) Thalassemia in Iran in last twenty years: the carrier rates and the births trend. Iran J Blood Cancer 6(1):11–17

    Google Scholar 

  • Muncie HL Jr, Campbell J (2009) Alpha and beta thalassemia. Am Fam Physician 80(4):339–344

    PubMed  Google Scholar 

  • Quan L, Lv Q, Zhang Y (2016) STRUM: structure-based prediction of protein stability changes upon single-point mutation. Bioinformatics 32(19):2936–2946

    Article  CAS  Google Scholar 

  • Saleh-Gohari N, Khosravi-Mashizi A (2010) Spectrum of α-globin gene mutations in the Kerman Province of Iran. Hemoglobin 34(5):451–460

    Article  CAS  Google Scholar 

  • Sanger F, Nicklen S, Coulson A (1992) DNA sequencing with chain-terminating inhibitors. Biotechnology 24:104

    CAS  PubMed  Google Scholar 

  • Vichinsky E (2010) Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. Ann N Y Acad Sci 1202(1):180–187

    Article  Google Scholar 

  • Vichinsky E (2012) Advances in the treatment of alpha-thalassemia. Blood Rev 26:S31–S34

    Article  CAS  Google Scholar 

  • Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF (2005) Changes in the epidemiology of thalassemia in North America: a new minority disease. Pediatrics 116(6):e818–e825

    Article  Google Scholar 

  • Zandian K, Nateghi J, Keikhaie B, Pedram M, Hafezi-Nejad N, Hadavi V et al (2008) α-thalassemia mutations in Khuzestan Province, Southwest Iran. Hemoglobin 32(6):546–552

    Article  CAS  Google Scholar 

  • Zeinalian M, Nobari RF, Moafi A, Salehi M, Hashemzadeh-Chaleshtori M (2013) Two decades of pre-marital screening for beta-thalassemia in central Iran. J Community Genet 4(4):517–522

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank all our colleagues in Shafa Hospital, Ahvaz, Iran.

Author information

Authors and Affiliations

  1. Research Center for Thalassemia and Hemoglobinopathy, Health Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Bijan Keikhaei & Pejman Slehi-fard

  2. Narges Genetic & PND Laboratory, Kianpars, East Mihan Street, Ahvaz, Iran

    Gholamreza Shariati

  3. Department of Medical Genetic, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Gholamreza Shariati

  4. Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran

    Abbas Khosravi

  5. Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Abbas Khosravi

Authors
  1. Bijan Keikhaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pejman Slehi-fard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gholamreza Shariati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abbas Khosravi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abbas Khosravi.

Ethics declarations

Conflict of interest

The authors declared no conflict of interest.

Ethical Standards

All procedures have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed Consent

Informed consent was signed prior to participation in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 11 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Keikhaei, B., Slehi-fard, P., Shariati, G. et al. Genetics of Iranian Alpha-Thalassemia Patients: A Comprehensive Original Study. Biochem Genet 56, 506–521 (2018). https://doi.org/10.1007/s10528-018-9857-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10528-018-9857-6

Keywords

Search

Navigation