# HBA1

## Overview
The HBA1 gene encodes the hemoglobin subunit alpha 1, a vital component of the hemoglobin protein complex responsible for oxygen transport in the bloodstream. This gene is located on chromosome 16 and plays a crucial role in the formation of hemoglobin tetramers, which consist of two alpha and two beta subunits. The protein product, α-globin, is categorized as a globin protein and is essential for the binding and release of oxygen, facilitating efficient oxygen delivery to tissues throughout the body (Farashi2018Molecular). Beyond its primary function in red blood cells, α-globin is also expressed in endothelial cells, where it interacts with endothelial nitric oxide synthase (eNOS) to modulate vascular tone and blood pressure (Lechauve2018Endothelial). Mutations in the HBA1 gene can lead to α-thalassemia and other hemoglobinopathies, highlighting its clinical significance in genetic disorders affecting hemoglobin function (Moradkhani2008Mutations; AbdulAzeez2016InSilico).

## Structure
The HBA1 gene encodes the hemoglobin subunit alpha 1, which is a crucial component of the hemoglobin molecule responsible for oxygen transport in the blood. The primary structure of the HBA1 protein consists of a specific sequence of amino acids that form the polypeptide chain. The secondary structure is predominantly composed of alpha helices, which are essential for the protein's stability and function (AbdulAzeez2016InSilico).

The tertiary structure of the HBA1 protein involves the three-dimensional folding of the polypeptide chain, which is necessary for its functional conformation. This folding allows the protein to interact with the heme group, a critical component for oxygen binding (Ropero2021Hb). The quaternary structure of hemoglobin involves the assembly of two alpha and two beta subunits, forming a tetrameric complex that facilitates efficient oxygen transport (HorriNaceur2020In).

Post-translational modifications, such as acetylation and phosphorylation, may occur, influencing the protein's function and stability. These modifications can affect the protein's interaction with other molecules and its overall activity in the hemoglobin complex (Farashi2015Identification). The HBA1 gene can also produce splice variant isoforms, which may result in different functional properties of the protein (Farashi2015Identification).

## Function
The HBA1 gene encodes the alpha subunit of hemoglobin, a critical protein for oxygen transport in red blood cells. In healthy human cells, the alpha subunit pairs with beta subunits to form hemoglobin tetramers, which are essential for binding oxygen in the lungs and releasing it in tissues, thereby facilitating cellular respiration and maintaining oxygen delivery throughout the body (Farashi2018Molecular).

Beyond its role in red blood cells, α-globin, the protein product of HBA1, is also expressed in endothelial cells (ECs) where it plays a role in regulating vascular function. In ECs, α-globin interacts with endothelial nitric oxide synthase (eNOS) to degrade nitric oxide (NO), a potent vasodilator, thus influencing vasoconstriction and vascular tone (Lechauve2018Endothelial). The stability and function of α-globin in these cells are supported by the α-hemoglobin-stabilizing protein (AHSP), which prevents its denaturation and degradation (Lechauve2018Endothelial). This interaction is crucial for maintaining normal blood pressure and vascular physiology, as evidenced by studies showing that mice lacking HBA1 or AHSP exhibit dilated arterioles and reduced blood pressure (Lechauve2018Endothelial).

## Clinical Significance
Mutations in the HBA1 gene can lead to α-thalassemia, a genetic disorder characterized by reduced or absent synthesis of α-globin proteins. This condition often results from deletional defects but can also arise from point mutations in the HBA1 gene (AbdulAzeez2016InSilico). Specific non-synonymous single nucleotide polymorphisms (nsSNPs) in the HBA1 gene, such as G60V and W15R, have been identified as highly deleterious, potentially causing structural and functional modifications in the HBA1 protein (AbdulAzeez2016InSilico). These mutations can lead to severe forms of α-thalassemia, such as hemoglobin H disease and hydrops fetalis, which are associated with significant clinical manifestations including anemia and, in severe cases, fetal death.

The HBA1 gene is also implicated in the development of various hemoglobin variants. Although many of these variants are clinically silent, some can cause conditions like hemolytic anemia, methemoglobinemia, cyanosis, or polycythemia (Moradkhani2008Mutations). The presence of these variants underscores the importance of genetic analysis in understanding the impact of HBA1 mutations on hemoglobin function and stability (Moradkhani2008Mutations).

## Interactions
The HBA1 gene encodes the alpha globin subunit, which is a component of hemoglobin. In human resistance arteries, alpha globin interacts with endothelial nitric oxide synthase (eNOS) to form a stable complex. This interaction is significant for regulating nitric oxide (NO) signaling and vasodilation. The complex formation has been confirmed through techniques such as fluorescence resonance energy transfer (FRET) and co-immunoprecipitation (Brooks2021Hemoglobin). 

Alpha globin also interacts with beta globin to form a heterotetrameric hemoglobin molecule, which can bind to an eNOS oxygenase homodimer. This complex is thought to play a role in the vasoregulatory function of human resistance arteries (Brooks2021Hemoglobin). 

The alpha-hemoglobin-stabilizing protein (AHSP) is another key interaction partner of alpha globin. AHSP stabilizes free alpha globin by preventing its aggregation and precipitation, which is crucial in endothelial cells where beta globin is absent. AHSP binds specifically to oxidized alpha globin, facilitating its reduction by eNOS, and plays a role in maintaining vascular tone by modulating NO availability (Lechauve2018Endothelial).


## References


[1. (Farashi2015Identification) Samaneh Farashi, Shadi Vakili, Negin F. Garous, Mehri Ashki, Fatemeh Forouzesh Pour, Fatemeh Zeinali, Fariba Rad, Hashem Imanian, Azita Azarkeivan, and Hossein Najmabadi. Identification of mutations causing aberrant termination and deficient splice donor site on thehba1gene. Hemoglobin, 40(1):38–43, November 2015. URL: http://dx.doi.org/10.3109/03630269.2015.1088456, doi:10.3109/03630269.2015.1088456. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3109/03630269.2015.1088456)

[2. (Lechauve2018Endothelial) Christophe Lechauve, Joshua T. Butcher, Abdullah Freiwan, Lauren A. Biwer, Julia M. Keith, Miranda E. Good, Hans Ackerman, Heather S. Tillman, Laurent Kiger, Brant E. Isakson, and Mitchell J. Weiss. Endothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractility. Journal of Clinical Investigation, 128(11):5073–5082, October 2018. URL: http://dx.doi.org/10.1172/jci99933, doi:10.1172/jci99933. This article has 40 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci99933)

3. (Brooks2021Hemoglobin) Hemoglobin Interacts with Endothelial Nitric Oxide Synthase to Regulate Vasodilation in Human Resistance Arteries. This article has 2 citations.

[4. (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)

[5. (Moradkhani2008Mutations) Kamran Moradkhani, Claude Préhu, John Old, Shirley Henderson, Vera Balamitsa, Hong-Yuan Luo, Man-Chiu Poon, David H. K. Chui, Henri Wajcman, and George P. Patrinos. Mutations in the paralogous human α-globin genes yielding identical hemoglobin variants. Annals of Hematology, 88(6):535–543, October 2008. URL: http://dx.doi.org/10.1007/s00277-008-0624-3, doi:10.1007/s00277-008-0624-3. This article has 39 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00277-008-0624-3)

[6. (HorriNaceur2020In) Agathe Horri-Naceur and David J. Timson. In silicoanalysis of the effects of point mutations on α-globin: implications for α-thalassemia. Hemoglobin, 44(2):89–103, March 2020. URL: http://dx.doi.org/10.1080/03630269.2020.1739067, doi:10.1080/03630269.2020.1739067. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/03630269.2020.1739067)

[7. (Ropero2021Hb) Paloma Ropero, Jorge M. Nieto, Fernando-Ataúlfo González Fernández, Ana Villegas, and Celina Benavente. Hb maruchi [α165 (e14) ala>pro; hba1: c.196g>c]: a new thalassemia hemoglobinopathy related to the alpha1 globin gene. Clinical Biochemistry, 92:77–81, June 2021. URL: http://dx.doi.org/10.1016/j.clinbiochem.2021.02.010, doi:10.1016/j.clinbiochem.2021.02.010. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.clinbiochem.2021.02.010)

[8. (AbdulAzeez2016InSilico) Sayed AbdulAzeez and J. Francis Borgio. In-silico computing of the most deleterious nssnps in hba1 gene. PLOS ONE, 11(1):e0147702, January 2016. URL: http://dx.doi.org/10.1371/journal.pone.0147702, doi:10.1371/journal.pone.0147702. This article has 36 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0147702)