Dear Editor,
The globin genes have a number of mutations and sequence variants, including a single base deletion in repetitive nucleotides. Here we report a kind of misperception reading, codon 35 (–C) vs. codon 36 (–C), and suggest how to overcome this case.
Thalassemia, a human hemoglobin (Hb) variant, is a disease found throughout the world, especially in countries along the so-called Thalassemia Belt (Citation1). Concern is not only in lifelong management, but also in the complexity of the disease due to many molecular aspects involved. To date, there are over 800 mutations and sequence variations in the β chain gene, updated regularly in HbVar (http://globin.cse.psu.edu/hbvar/menu.html) (Citation2). An article titled “A new β-thalassemia deletion mutation [codon 36 (–C)] observed in a Chinese woman” (Citation3), claimed that they found a novel deletion at codon 36 in the β chain, leading to a premature stop codon. The same authors also published another article titled “Molecular epidemiological analysis of α- and β-thalassemia in Fujian Province” (Citation4) on the same interpretation. However, if we look at the sequences, we can figure it also as codon 35 (–C), a common mutation that has been well established in HbVar, in which the bases stretch from codons 34 to 37 (5′-GTC TAC CCT TGG-3′). There are triple Cs in codon 35 and codon 36, and we cannot define precisely which base is actually deleted.
The mutation at codon 35 results in GTC TAC CTT GG; in codon 36, either the first or second C, also results in GTC TAC CTT GG. Both types of mutation result in a premature stop codon at codon 60 (Citation3,Citation5). We therefore propose that the best conclusion in this issue is to define the mutation as codon 35 (–C) mutation, a well established nomenclature, instead of codon 36 (–C).
Another variation is still possible for the misperception reading as in this case. For example, a deletion of G at codon 1 (–G); GTG>–TG can be misinterpreted by deletion of the last G at the start codon ATG. In the same way, a deletion of G at codon 104 (AGG), can also be disrupted by deletion of base G at the next codon (GTG). On the other hand, mutations on the α gene, a paralogous gene with two identical sequences of α1 and α2, can result in a misinterpretation mutation, whether in HBA1 or HBA2. For this information, a comprehensive proposal has been submited for suitable nomenclature by Moradkhani and coworkers (Citation6).
This has actually highlighted potential confusion with the nomenclature of any deletion mutations involving repetitive nucleotides such as in this example. For curating purpose, this example suggests that no novel deletion mutations could be assigned within any repetitive nucleotides where a deletion mutation has already been described. We suggest that in addition to using traditional names that are familiar, the authors are encouraged to include the name of the Human GenomeVariation Sopiety (HGVS) nomenclature that is designed to prevent these errors by providing a clear set of rules across all variants (http://www.hgvs.org/mutnomen/). In this case, the 3′ end position must be used (Citation7).
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References
- Weatherall DJ. Thalassemia as a global health problem: Recent progress toward its control in the developing countries. Ann N Y Acad Sci. 2010;1202:17–23
- Giardine B, Borg J, Viennas E, et al. Updates of the HbVar database of human hemoglobin variants and thalassemia mutations. Nucleic Acids Res. 2014;42(Database issue):D1063–D1069. ( http://globin.cse.psu.edu)
- Huang H, Xu L, Lin N, et al. A new β-thalassemia deletion mutation [codon 36 (–C)] observed in a Chinese woman. Hemoglobin. 2010;34(6):599–603
- Xu L, Huang H, Wang Y, et al. Molecular epidemiological analysis of α- and β-thalassemia in Fujian Province. Chinese J Med Genet. 2013;30(4):403–406
- Yang KG, Kutlar F, George E, et al. Molecular characterization of β-globin gene mutations in Malay patients with Hb E-β-thalassaemia and thalassaemia major. Br J Haematol. 1989;72(1):73–80
- Moradkhani K, Préhu C, Old J, et al. Mutations in the paralogous human α-globin genes yielding identical hemoglobin variants. Ann Hematol. 2009;88(6):535–543
- den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion. Hum Mutat. 2000;15(1):7–12. [Erratum in: Hum Mutat. 2002;20(5):403]