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  • Writer's pictureAva GianGrasso

Beta-Thalassemia: An Overview

Updated: Aug 29, 2023

Beta-thalassemia is one of most common autosomal recessive disorders worldwide, prominent in the Middle East, Central Asia, and the Mediterranean. There are different conditions of thalassemia, including the beta-thalassemia carrier state, thalassemia intermedia, and thalassemia major (Cao and Galanello 2010). Those who are homozygotes for beta-thalassemia may develop either thalassemia intermediate or major, characterized by reduced synthesis of the hemoglobin beta chain caused by mutations in the human globin gene, HBB (Origa 1993; George Priya Doss C., and Rao 2009). Those who present symptoms may experience pale skin, growth issues, skeletal changes, and internal organ abnormality, with thalassemia major causing the most severe complications. The disease causes low levels of hemoglobin in the body, which reduces oxygen levels. Worldwide, about 1 in 100,000 people are symptomatic for beta-thalassemia (Galanello and Origa 2010).


The HBB gene is found on chromosome 11 and over 200 beta-thalassemia-causing mutations have been identified, consisting of frameshift mutations (such as deletions and additions) and substitutions of nucleotide base(s) in the gene. These mutations can be classified in three ways: those that lead to incorrect beta-gene transcription, those that affect mRNA processing, and those that alter mRNA translation (Cao and Galanello 2010). A lesser-known possible cause for beta-thalassemia is a conformational change in the RNA structure, although this has not been investigated as deeply (Halvorsen et al. 2010). Most often, beta-thalassemia is the result of a mutation in the HBB gene sequence that can have major consequences.


In various parts of the world, different mutations that lead to beta-thalassemia are prominent. For example, in the Kermanshah Province of Iran, substituting adenine for guanine, or simply the deletion of a guanine in the gene sequence, accounted for almost 50% of beta-thalassemia cases (Rahimi et al. 2010). In other areas, such as Sabah, Malaysia, it was found that individuals with severe beta-thalassemia all had a rare major deletion within the HBB gene instead of solely frameshift mutations (Thong et al. 1999).


What and where mutations occur in the gene determines how severe the beta-thalassemia is and what mechanisms are defected. For example, when beta-thalassemia is caused due to the complete absence of beta chain production, this can be traced back to frameshift and splicing mutations at the splice site junction of the HBB gene. Yet, when beta-thalassemia is the consequence of reduced beta-chain production, the culprit is usually a mutation in the promoter area (Cao and Galanello 2010). Overall, the extent to which the HBB gene is mutated dictates how reduced the beta chain output is. The more reduced the output, the more severe the symptoms (Rahimi et al. 2010).


There is still much to discover about beta-thalassemia mutations. Although many mutations consist of discoverable single frameshift mutations, there has been research on silent mutations as well. Silent mutations are not commonly detected in beta-thalassemia screening and most commonly affect those with beta-thalassemia intermedia. These mutations often reduce efficiency of translation and may even disrupt the function of downstream core elements in the gene (Sgourou et al. 2004). There have also been rare instances in which the beta-thalassemia defect does not lie in the HBB gene or in the beta-globin gene cluster, but an X-linked transcription factor GATA-1 instead (Origa 1993).

Mutations in the HBB gene may not always result in beta-thalassemia. Other phenotypes associated with variants in the HBB gene are sickle cell disease, caused by an adenine to thymine substitution at codon 6, and Hemoglobin E, caused by a nucleotide substitution at codon 26 (Orgia 1993). Whatever the disease may be, mutations in the HBB gene can cause severe health problems and frequently require blood transfusions to give people the best quality of life possible (Galanello and Orgia 2010).


Ava GianGrasso is a freshman at Washington & Lee University. She serves as the W&L division's Managing Editor.

Literature Cited


Cao A., and R. Galanello, 2010 Beta-thalassemia. Genetics in Medicine 12: 61–76. https://doi.org/10.1097/GIM.0b013e3181cd68ed


Galanello R., and R. Origa, 2010 Beta-thalassemia. Orphanet J Rare Dis 5: 11. https://doi.org/10.1186/1750-1172-5-11


George Priya Doss C., and S. Rao, 2009 Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. New Biotechnology 25: 214–219. https://doi.org/10.1016/j.nbt.2009.01.004


Halvorsen M., J. S. Martin, S. Broadaway, and A. Laederach, 2010 Disease-associated mutations that alter the RNA structural ensemble. PLoS Genetics 6. https://doi.org/10.1371/journal.pgen.1001074


Origa R., 1993 Beta-Thalassemia, in GeneReviews®, edited by Adam M. P., Everman D. B., Mirzaa G. M., Pagon R. A., Wallace S. E., et al. University of Washington, Seattle, Seattle (WA).

Rahimi Z., A. Muniz, and A. Parsian, 2010 Detection of responsible mutations for beta thalassemia in the Kermanshah Province of Iran using PCR-based techniques. Molecular Biology Reports 37: 149–154. https://doi.org/10.1007/s11033-009-9560-0


Sgourou A., S. Routledge, M. Antoniou, A. Papachatzopoulou, L. Psiouri, et al., 2004 Thalassaemia mutations within the 5′UTR of the human β-globin gene disrupt transcription. British Journal of Haematology 124: 828–835. https://doi.org/10.1111/j.1365-2141.2004.04835.x


Thong M. K., Z. Rudzki, J. Hall, J. A. Tan, L. L. Chan, et al., 1999 A single, large deletion accounts for all the beta-globin gene mutations in twenty families from Sabah (North Borneo), Malaysia. Mutation in brief no. 240. Online. Human mutation 13: 413. https://doi.org/10.1002/(SICI)1098-1004(1999)13:5<413::AID-HUMU14>3.0.CO;2-H


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