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Hemoglobin
international journal for hemoglobin research
Volume 44, 2020 - Issue 2
133
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Original Articles

In Silico Analysis of the Effects of Point Mutations on α-Globin: Implications for α-Thalassemia

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Pages 89-103 | Received 22 Nov 2019, Accepted 22 Feb 2020, Published online: 18 May 2020
 

Abstract

Hemoglobinopathies are inherited diseases that impair the structure and function of the oxygen-carrying pigment hemoglobin (Hb). Adult Hb consists of two α and two β subunits. α-Thalassemia (α-thal) affects the genes that code for the α-globin chains, HBA1 and HBA2. Mutations can result in asymptomatic, mild or severe outcomes depending on several factors, such as mutation type, number of mutations and the location at which they occur. PredictSNP was used to estimate whether every possible single nucleotide polymorphism (SNP) would have a neutral or deleterious effect on the protein. These results were then used to create a plot of predicted tolerance to change for each residue in the protein. Tolerance to change was negatively correlated with the residue’s sequence conservation score. The PredictSNP data were compared to clinical reports of 110 selected variants in the literature. There were 29 disagreements between the two data types. Some of these could be resolved by considering the role of the affected residue in binding other molecules. The three-dimensional structures of some of these variant proteins were modeled. These models helped explain variants which affect heme binding. We predict that where a point mutation alters a residue that is intolerant to change, is well conserved and or involved in interactions, it is likely to be associated with disease. Overall, the data from this study could be used alongside biochemical and clinical data to assess novel α-globin variants.

Acknowledgments

The authors thank the scientists who wrote and freely provided the software tools used in this project.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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