# HBA2

## Overview
The HBA2 gene encodes the hemoglobin subunit alpha 2, a critical component of the hemoglobin protein complex responsible for oxygen transport in vertebrate red blood cells. This gene is located on chromosome 16 and is one of two alpha globin genes, the other being HBA1. The protein product, hemoglobin subunit alpha 2, is categorized as a globin protein and forms part of the tetrameric structure of hemoglobin, which includes two alpha and two beta chains. This structure is essential for the protein's function in binding and releasing oxygen, facilitating efficient oxygen delivery from the lungs to tissues throughout the body. The HBA2 gene is more transcriptionally active than HBA1, although the translation efficiency results in a balanced production of the alpha globin chains. Mutations in HBA2 can lead to various hematological disorders, including alpha-thalassemia, highlighting its clinical significance in maintaining normal hemoglobin function and erythrocyte stability (Singh2018Hb; Farashi2018Molecular).

## Structure
The HBA2 gene encodes the hemoglobin subunit alpha 2, which is a component of the hemoglobin protein responsible for oxygen transport in the blood. The primary structure of the HBA2 protein consists of a specific sequence of amino acids that form the alpha chain of hemoglobin. The secondary structure is characterized by the presence of alpha helices, which contribute to the protein's overall stability and function. The tertiary structure of the HBA2 protein results in a globular shape, which is typical for hemoglobin subunits. 

In terms of quaternary structure, the HBA2 protein assembles with two beta chains to form the functional hemoglobin tetramer, which is essential for its role in oxygen transport. This assembly involves specific interactions between the alpha and beta chains, contributing to the protein's stability and function (Sen2004Crystal).

Post-translational modifications of the HBA2 protein include acetylation and phosphorylation, which can influence the protein's function and interactions. These modifications are common in hemoglobin subunits and play a role in regulating the protein's activity and stability. The structural characteristics of HBA2, including its specific domains and prominent folds, are crucial for its role in maintaining the proper function of hemoglobin in oxygen transport.

## Function
The HBA2 gene encodes the alpha 2 subunit of hemoglobin, which plays a crucial role in oxygen transport in red blood cells. Hemoglobin is a tetramer composed of two alpha and two beta chains, and the alpha 2 subunit is essential for binding oxygen in the lungs and releasing it in tissues, facilitating cellular respiration and energy production (Farashi2018Molecular).

In healthy human cells, the HBA2 gene is more transcriptionally active than its counterpart, HBA1, with a typical mRNA ratio of 70% to 30%. However, due to less efficient translation of HBA2 mRNA, the protein level contributions are more balanced, resulting in a 60% to 40% ratio (Farashi2018Molecular). The HBA2 subunit is involved in multiple protein-protein interactions, including with hemoglobin beta (HBB) and alpha hemoglobin stabilizing protein (AHSP), which help maintain hemoglobin stability and prevent oxidative stress (Fitzsimmons2016Understanding).

HBA2 also plays a role in inhibiting sickle cell polymerization by preventing the formation of asymmetrical hybrids with sickle hemoglobin (HbS), which are crucial for the polymerization process that leads to sickle cell disease (Sen2004Crystal). This antisickling effect is attributed to specific residues in the HBA2 subunit that create unfavorable contacts with HbS, inhibiting polymer formation (Sen2004Crystal).

## Clinical Significance
Mutations in the HBA2 gene, which encodes the alpha-2 globin chain, are associated with several hematological disorders, primarily alpha-thalassemia. Alpha-thalassemia is characterized by reduced or absent production of alpha globin, leading to unstable hemoglobin tetramers and varying degrees of anemia (Singh2018Hb). Nondeletional mutations, such as Hb Adana, can result in more severe disease phenotypes compared to deletional mutations, especially when combined with other genetic alterations (Singh2018Hb).

A specific mutation in the HBA2 gene, HBA2: c.94A>G, has been identified as causing a frameshift and premature termination codon, leading to rapid degradation of the aberrantly spliced transcripts by the nonsense-mediated decay system. This mutation is associated with an alpha-thalassemia phenotype and can result in clinical symptoms such as splenomegaly, microcytosis, and hypochromia (Qadah2013Molecular).

Additionally, mutations in the HBA2 gene can lead to high oxygen affinity hemoglobin (HOAH), which causes tissue hypoxia and secondary erythrocytosis. This condition can be asymptomatic or lead to significant erythrocytosis, necessitating careful genetic analysis for accurate diagnosis (Filser2022Importance).

## Interactions
The HBA2 gene encodes the alpha-2 subunit of hemoglobin, which participates in several important protein interactions. One significant interaction is with erythroid spectrin, a cytoskeletal protein that plays a crucial role in maintaining the structural integrity of erythrocyte membranes. Studies have shown that spectrin has a higher affinity for hemoglobin A2 (HbA2), which includes the alpha-2 subunit, compared to other hemoglobin variants. This interaction is particularly relevant in the context of β-thalassemia, where elevated levels of HbA2 are observed. The increased binding affinity between spectrin and HbA2 may contribute to the mechanical properties of the erythrocyte membrane and is implicated in the pathology of β-thalassemia (Datta2003Interaction).

Spectrin also exhibits chaperone-like activity, particularly towards free α-globin chains, which are components of the HBA2 gene product. This interaction is ATP-dependent and aids in the refolding of denatured α-globin chains, which is significant in conditions like thalassemia where excess α-globin chains are prone to aggregation (Basu2015Hemoglobin). These interactions highlight the role of HBA2 in maintaining hemoglobin stability and erythrocyte membrane integrity.


## References


[1. (Sen2004Crystal) Udayaditya Sen, Jhimli Dasgupta, Debi Choudhury, Poppy Datta, Abhijit Chakrabarti, Sudipa Basu Chakrabarty, Amit Chakrabarty, and Jiban K. Dattagupta. Crystal structures of hba2 and hbe and modeling of hemoglobin δ4: interpretation of the thermal stability and the antisickling effect of hba2 and identification of the ferrocyanide binding site in hb. Biochemistry, 43(39):12477–12488, September 2004. URL: http://dx.doi.org/10.1021/bi048903i, doi:10.1021/bi048903i. This article has 40 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi048903i)

[2. (Fitzsimmons2016Understanding) Reis Fitzsimmons, Narmin Amin, and Vladimir N. Uversky. Understanding the roles of intrinsic disorder in subunits of hemoglobin and the disease process of sickle cell anemia. Intrinsically Disordered Proteins, 4(1):e1248273, January 2016. URL: http://dx.doi.org/10.1080/21690707.2016.1248273, doi:10.1080/21690707.2016.1248273. This article has 9 citations.](https://doi.org/10.1080/21690707.2016.1248273)

[3. (Farashi2018Molecular) Samaneh Farashi and Cornelis L. Harteveld. Molecular basis of α-thalassemia. Blood Cells, Molecules, and Diseases, 70:43–53, May 2018. URL: http://dx.doi.org/10.1016/j.bcmd.2017.09.004, doi:10.1016/j.bcmd.2017.09.004. This article has 143 citations.](https://doi.org/10.1016/j.bcmd.2017.09.004)

[4. (Basu2015Hemoglobin) Avik Basu and Abhijit Chakrabarti. Hemoglobin interacting proteins and implications of spectrin hemoglobin interaction. Journal of Proteomics, 128:469–475, October 2015. URL: http://dx.doi.org/10.1016/j.jprot.2015.06.014, doi:10.1016/j.jprot.2015.06.014. This article has 29 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jprot.2015.06.014)

[5. (Qadah2013Molecular) Talal Qadah, Jill Finlayson, Philippe Joly, and Reza Ghassemifar. Molecular and cellular analysis of a novelhba2mutation (hba2: c.94a>g) shows activation of a cryptic splice site and generation of a premature termination codon. Hemoglobin, 38(1):13–18, November 2013. URL: http://dx.doi.org/10.3109/03630269.2013.858639, doi:10.3109/03630269.2013.858639. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3109/03630269.2013.858639)

[6. (Filser2022Importance) Mathilde Filser, Betty Gardie, Mathieu Wemeau, Patricia Aguilar-Martinez, Muriel Giansily-Blaizot, and François Girodon. Importance of sequencing hba1, hba2 and hbb genes to confirm the diagnosis of high oxygen affinity hemoglobin. Genes, 13(1):132, January 2022. URL: http://dx.doi.org/10.3390/genes13010132, doi:10.3390/genes13010132. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/genes13010132)

[7. (Datta2003Interaction) Poppy Datta, Sudipa Basu Chakrabarty, Amit Chakrabarty, and Abhijit Chakrabarti. Interaction of erythroid spectrin with hemoglobin variants: implications in β-thalassemia. Blood Cells, Molecules, and Diseases, 30(3):248–253, May 2003. URL: http://dx.doi.org/10.1016/s1079-9796(03)00019-6, doi:10.1016/s1079-9796(03)00019-6. This article has 26 citations.](https://doi.org/10.1016/s1079-9796(03)00019-6)

[8. (Singh2018Hb) Sharon A. Singh, Susmita Sarangi, Abena Appiah‐Kubi, Peihong Hsu, W. Byron Smith, Patrick G. Gallagher, Bertil Glader, and David H. K. Chui. Hb adana (hba2 or hba1: c.179g > a) and alpha thalassemia: genotype–phenotype correlation. Pediatric Blood & Cancer, May 2018. URL: http://dx.doi.org/10.1002/pbc.27220, doi:10.1002/pbc.27220. This article has 14 citations.](https://doi.org/10.1002/pbc.27220)