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.
Alpha thalassemia Genotype Phenotype Southwest of Iran
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The authors wish to thank all our colleagues in Shafa Hospital, Ahvaz, Iran.
Compliance with Ethical Standards
Conflict of interest
The authors declared no conflict of interest.
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 was signed prior to participation in the study.
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):162PubMedPubMedCentralGoogle Scholar
Alibakhshi R, Mehrabi M, Omidniakan L, Shafieenia S (2015) The spectrum of α-thalassemia mutations in Kermanshah Province, West Iran. Hemoglobin 39(6):403–406CrossRefPubMedGoogle 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):148–159PubMedGoogle 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):e1003440CrossRefPubMedPubMedCentralGoogle 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–W310CrossRefPubMedPubMedCentralGoogle Scholar
Chui DH, Fucharoen S, Chan V (2003) Hemoglobin H disease: not necessarily a benign disorder. Blood 101(3):791–800CrossRefPubMedGoogle 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. 2013:858294CrossRefPubMedPubMedCentralGoogle 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):327–329CrossRefGoogle 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):355–358PubMedGoogle 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 2015:517679CrossRefPubMedPubMedCentralGoogle 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):82–85CrossRefPubMedGoogle 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):153–157CrossRefPubMedGoogle 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):139–143CrossRefPubMedGoogle 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):1215–1221CrossRefPubMedGoogle 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/zjms1032Google 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):192–195CrossRefPubMedGoogle 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):161–164CrossRefPubMedGoogle 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):113–117CrossRefPubMedGoogle 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 6:26371CrossRefPubMedPubMedCentralGoogle 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):1057CrossRefPubMedPubMedCentralGoogle 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):295–299CrossRefPubMedGoogle 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):15245–15254PubMedGoogle 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):11–17Google Scholar
Muncie HL Jr, Campbell J (2009) Alpha and beta thalassemia. Am Fam Physician 80(4):339–344PubMedGoogle 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–e825CrossRefPubMedGoogle 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):546–552CrossRefPubMedGoogle 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):517–522CrossRefPubMedPubMedCentralGoogle Scholar