Hemoglobin subunit beta

{{main|Human β-globin locus}}

Beta-globin is produced by the gene HBB which is located in the multigene locus of β-globin locus on chromosome 11, specifically on the short arm position 15.4. Expression of beta globin and the neighbouring globins in the β-globin locus is controlled by single locus control region (LCR), the most important regulatory element in the locus located upstream of the globin genes.{{cite journal | vauthors= Levings PP, Bungert J | title = The human beta-globin locus control region | journal = Eur. J. Biochem. | volume = 269 | issue = 6 | pages = 1589–99 | year = 2002 | pmid = 11895428 | doi = 10.1046/j.1432-1327.2002.02797.x | doi-access = free }} The normal allelic variant is 1600 base pairs (bp) long and contains three exons. The order of the genes in the beta-globin cluster is 5' - epsilon – gamma-G – gamma-A – delta – beta - 3'.

Beta-globin interacts with alpha-globin to form haemoglobin A, the major haemoglobin in adult humans.{{cite journal | vauthors= Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE | title = A human protein-protein interaction network: a resource for annotating the proteome | journal = Cell | volume = 122 | issue = 6 | pages = 957–968 | year = 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 | hdl = 11858/00-001M-0000-0010-8592-0 | s2cid = 8235923 | hdl-access = free }}{{cite journal | vauthors= Shaanan B | title = Structure of human oxyhaemoglobin at 2.1 A resolution | journal = J. Mol. Biol. | volume = 171 | issue = 1 | pages = 31–59 | year = 1983 | pmid = 6644819 | doi = 10.1016/S0022-2836(83)80313-1 | location = England | issn = 0022-2836 }} The interaction is two-fold. First, one β-globin molecule and one α-globin molecule combine by electrostatic attraction to form a dimer.{{cite journal | vauthors = Bunn HF | title = Subunit assembly of hemoglobin: an important determinant of hematologic phenotype | journal = Blood | volume = 69 | issue = 1 | pages = 1–6 | date = January 1987 | pmid = 3539223 | url = https://pubmed.ncbi.nlm.nih.gov/3539223 }} Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemoglobin.{{cite web|title=Hemoglobin Synthesis|url=http://sickle.bwh.harvard.edu/hbsynthesis.html|website=harvard.edu|publisher=Harvard University|access-date=18 November 2014|date=2002}}

{{Main|Beta thalassemia}}

Beta thalassemia is an inherited genetic mutation in one (Beta thalassemia minor) or both (Beta thalassemia major) of the Beta globin alleles on chromosome 11. The mutant alleles are subdivided into two groups: β0, in which no functional β-globin is made, and β+, in which a small amount of normal β-globin protein is produced. Beta thalassemia minor occurs when an individual inherits one normal Beta allele and one abnormal Beta allele (either β0, or β+). Beta thalassemia minor results in a mild microcytic anemia that is often asymptomatic or may cause fatigue and or pale skin. Beta thalassemia major occurs when a person inherits two abnormal alleles. This can be either two β+ alleles, two β0 alleles, or one of each. Beta thalassemia major is a severe medical condition. A severe anemia is seen starting at 6 months of age. Without medical treatment death often occurs before age 12. {{cite book | author1= H. Franklin Bunn |author2=Vijay G. Sankaran| title = Pathology of blood disorders| chapter= 8| pages = 927–933 | year = 2017 }} Beta thalassemia major can be treated by lifelong blood transfusions or bone marrow transplantation.{{cite journal | vauthors= Muncie HL, Campbell J | title = Alpha and beta thalassemia | journal = American Family Physician | volume = 80 | issue = 4 | pages = 339–44 | year = 2009 | pmid = 19678601 }}{{cite web|title=Beta thalassemia|url=http://ghr.nlm.nih.gov/condition/beta-thalassemia|work=Genetics Home Reference|publisher=U.S. National Library of Medicine|access-date=18 November 2014|date=11 November 2014}}

{{Main|Sickle cell disease}}

More than a thousand naturally occurring HBB variants have been discovered. The most common is HbS, which causes sickle cell disease. HbS is produced by a point mutation in HBB in which the codon GAG is replaced by GTG. This results in the replacement of hydrophilic amino acid glutamic acid with the hydrophobic amino acid valine at the seventh position (β6Glu→Val). This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent hemoglobin molecule's beta chain. This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire red blood cells in the homozygous (HbS/HbS) condition.{{cite journal | vauthors= Thom CS, Dickson CF, Gell DA, Weiss MJ | title = Hemoglobin variants: biochemical properties and clinical correlates | journal = Cold Spring Harb Perspect Med | volume = 3 | issue = 3 | pages = a011858 | year = 2013 | pmid = 23388674 | doi = 10.1101/cshperspect.a011858 | pmc=3579210}} The homozygous allele has become one of the deadliest genetic factors,{{cite journal | vauthors= Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De León FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA | title = Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 | journal = Lancet | volume = 380 | issue = 9859 | pages = 2095–128 | year = 2012 | pmid = 23245604 | doi = 10.1016/S0140-6736(12)61728-0 | pmc = 10790329 | hdl = 10536/DRO/DU:30050819 | s2cid = 1541253 | url = https://zenodo.org/record/2557786 | hdl-access = free }} whereas people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia.{{cite journal | vauthors= Luzzatto L | title = Sickle cell anaemia and malaria | journal = Mediterr J Hematol Infect Dis | volume = 4 | issue = 1 | pages = e2012065 | year = 2012 | pmid = 23170194 | pmc = 3499995 | doi = 10.4084/MJHID.2012.065 }}

{{Main|Hemoglobin C}}

Sickle cell disease is closely related to another mutant haemoglobin called haemoglobin C (HbC), because they can be inherited together.{{cite journal | vauthors= Piel FB, Howes RE, Patil AP, Nyangiri OA, Gething PW, Bhatt S, Williams TN, Weatherall DJ, Hay SI | title = The distribution of haemoglobin C and its prevalence in newborns in Africa | journal = Scientific Reports | volume = 3 | issue = 1671 | pages = 1671 | date = 2013 | pmid = 23591685 | pmc = 3628164 | doi = 10.1038/srep01671 | bibcode = 2013NatSR...3E1671P }} HbC mutation is at the same position in HbS, but glutamic acid is replaced by lysine (β6Glu→Lys). The mutation is particularly prevalent in West African populations. HbC provides near full protection against Plasmodium falciparum in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals.{{cite journal | vauthors= Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M | title = Haemoglobin C protects against clinical Plasmodium falciparum malaria | journal = Nature | volume = 414 | issue = 6861 | pages = 305–308 | date = 2001 | pmid = 11713529 | doi = 10.1038/35104556 | bibcode = 2001Natur.414..305M | s2cid = 4360808 }} This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions.{{cite journal | vauthors= Verra F, Bancone G, Avellino P, Blot I, Simporé J, Modiano D | title = Haemoglobin C and S in natural selection against Plasmodium falciparum malaria: a plethora or a single shared adaptive mechanism? | journal = Parassitologia | volume = 49 | issue = 4 | pages = 209–13 | date = 2007 | pmid = 18689228 }}

{{Main|Hemoglobin E}}

Another point mutation in HBB, in which glutamic acid is replaced with lysine at position 26 (β26Glu→Lys), leads to the formation of haemoglobin E (HbE).{{cite journal|vauthors=Olivieri NF, Pakbaz Z, Vichinsky E|title=Hb E/beta-thalassaemia: a common & clinically diverse disorder|journal=The Indian Journal of Medical Research|date=2011|volume=134|issue=4|pages=522–531|pmid=22089616|pmc=3237252}} HbE has a very unstable α- and β-globin association. Even though the unstable protein itself has mild effect, inherited with HbS and thalassemia traits, it turns into a life-threatening form of β-thalassemia. The mutation is of relatively recent origin suggesting that it resulted from selective pressure against severe falciparum malaria, as heterozygous allele prevents the development of malaria.{{cite journal|vauthors=Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J, Looareesuwan S, White N|title=Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria|journal=Blood|year=2002|volume=100|issue=4|pages=1172–1176|pmid=12149194|doi=10.1182/blood.V100.4.1172.h81602001172_1172_1176|doi-access=free}}

{{Main|Malaria resistance}}

Malaria due to Plasmodium falciparum is a major selective factor in human evolution.{{cite journal | vauthors = Verra F, Mangano VD, Modiano D | title = Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies | journal = Parasite Immunology | volume = 31 | issue = 5 | pages = 234–253 | date = May 2009 | pmid = 19388945 | doi = 10.1111/j.1365-3024.2009.01106.x | s2cid = 23734166 }} It has influenced mutations in HBB in various degrees resulting in the existence of numerous HBB variants. Some of these mutations are not directly lethal and instead confer resistance to malaria, particularly in parts of the world where malaria is epidemic.{{cite journal | vauthors = Tishkoff SA, Williams SM | title = Genetic analysis of African populations: human evolution and complex disease | journal = Nature Reviews. Genetics | volume = 3 | issue = 8 | pages = 611–621 | date = August 2002 | pmid = 12154384 | doi = 10.1038/nrg865 | s2cid = 7801737 }}{{cite journal | vauthors = Rao E, Kumar Chandraker S, Misha Singh M, Kumar R | title = Global distribution of β-thalassemia mutations: An update | journal = Gene | volume = 896 | pages = 148022 | date = February 2024 | pmid = 38007159 | doi = 10.1016/j.gene.2023.148022 }} For example, there is evidence that the sickle cell mutation, common in people of African descent, provides a degree of resistance to severe malaria.{{cite journal | vauthors = Luzzatto L | title = Sickle cell anaemia and malaria | journal = Mediterranean Journal of Hematology and Infectious Diseases | volume = 4 | issue = 1 | pages = e2012065 | date = 2012-10-03 | pmid = 23170194 | pmc = 3499995 | doi = 10.4084/mjhid.2012.065 }} Thus, HBB mutations are the sources of positive selection in these regions and are important for their long-term survival.{{cite journal | vauthors = Excoffier L | title = Human demographic history: refining the recent African origin model | journal = Current Opinion in Genetics & Development | volume = 12 | issue = 6 | pages = 675–682 | date = December 2002 | pmid = 12433581 | doi = 10.1016/S0959-437X(02)00350-7 }} Such selection markers are important for tracing human ancestry and diversification from Africa.{{cite journal | vauthors = Reed FA, Tishkoff SA | title = African human diversity, origins and migrations | journal = Current Opinion in Genetics & Development | volume = 16 | issue = 6 | pages = 597–605 | date = December 2006 | pmid = 17056248 | doi = 10.1016/j.gde.2006.10.008 }}

• Hemoglobin subunit alpha
• Human β-globin locus

{{reflist}}

{{refbegin|30em}}

• {{cite journal | vauthors = Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ | title = A review of the molecular genetics of the human alpha-globin gene cluster | journal = Blood | volume = 73 | issue = 5 | pages = 1081–1104 | date = April 1989 | pmid = 2649166 | doi = 10.1182/blood.V73.5.1081.1081 | doi-access = free }}
• {{cite journal | vauthors = Giardina B, Messana I, Scatena R, Castagnola M | title = The multiple functions of hemoglobin | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 30 | issue = 3 | pages = 165–196 | year = 1995 | pmid = 7555018 | doi = 10.3109/10409239509085142 }}
• {{cite journal | vauthors = Salzano AM, Carbone V, Pagano L, Buffardi S, De RC, Pucci P | title = Hb Vila Real [beta36(C2)Pro-->His] in Italy: characterization of the amino acid substitution and the DNA mutation | journal = Hemoglobin | volume = 26 | issue = 1 | pages = 21–31 | date = February 2002 | pmid = 11939509 | doi = 10.1081/HEM-120002937 | s2cid = 40757080 }}
• {{cite journal | vauthors = Frischknecht H, Dutly F | title = A 65 bp duplication/insertion in exon II of the beta globin gene causing beta0-thalassemia | journal = Haematologica | volume = 92 | issue = 3 | pages = 423–424 | date = March 2007 | pmid = 17339197 | doi = 10.3324/haematol.10785 | doi-access = free }}

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• {{PDBe-KB2|P68871|Human Hemoglobin subunit beta}}
• {{PDBe-KB2|P02088|Mouse Hemoglobin subunit beta-1}}

{{Commons category|Hemoglobin, beta-chain}}

{{PDB Gallery|geneid=3043}}

{{Hemeproteins}}

Category:Hemoglobins