HBB

For other uses, see HBB (disambiguation).
Hemoglobin, beta

HBB structure based on PyMOL rendering of PDB 1a00
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HBB ; CD113t-C; beta-globin
External IDs OMIM: 141900 MGI: 96022 HomoloGene: 68066 ChEMBL: 4331 GeneCards: HBB Gene
Orthologs
Species Human Mouse
Entrez 3043 15129
Ensembl ENSG00000244734 ENSMUSG00000052305
UniProt P68871 P02088
RefSeq (mRNA) NM_000518 NM_008220
RefSeq (protein) NP_000509 NP_032246
Location (UCSC) Chr 11:
5.25 – 5.25 Mb		 Chr 7:
103.81 – 103.81 Mb
PubMed search

Beta globin (also referred to as HBB, β-globin, haemoglobin beta, hemoglobin beta, or preferably haemoglobin subunit beta) is a globin protein, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, the HbA.[1] It is 146 amino acids long and has a molecular weight of 15,867 Da. Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains.

HBB is encoded by the HBB gene on human chromosome 11. Mutations in the gene produce several variants of the proteins which are implicated with genetic disorders such as sickle-cell disease and beta thalassemia, as well as beneficial traits such as genetic resistance to malaria.[2][3]

Gene locus

HBB protein 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 15.5. 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.[4] 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'.[1]

Interactions

HBB interacts with Hemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans.[5][6] The interaction is two-fold. First, one HBB and one HBA1 combine to form a single polypetide chain (dimer). Secondly, two dimers combine to form a larger polypeptide (tetramer), and this becomes the functional haemolglobin.[7]

Associated genetic disorders

Beta thalassemia

Total or partial absence of HBB causes a genetic disease called beta thalassemia. Total loss called, thalassemia major or beta-0-thalassemia, is due to mutation in both alleles, and this results in failure to form beta chain of haemoglobin. It prevents oxygen supply in the tissues. It is highly lethal. Symptoms, such as severe anaemia and heart attack, appear within two years after birth. They can be treated only by life-long blood transfusion and bone marrow transplantation.[8][9] Reduced HBB function called thalassemia minor or beta+ thalassemia is due to mutation in one of the alleles. It is less severe but patients are prone to other diseases such as asthma and liver problems.[10]

Haemoglobin C

Sickle cell disease is closely related to another mutant haemoglobin called haemoglobin C (HbC), because they can be inherited together.[11] HbC mutation is at the same position in HBB, 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.[12] This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions.[13]

Haemoglobin 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).[14] 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.[15]

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 sixth position (β6Glu→Val). This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent haemoglobin 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.[16] Homozygous allele has become one of the deadliest genetic factors.[17] Whereas, people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia.[18]

Human evolution

Malaria due to Plasmodium falciparum is a major selective factor in human evolution.[3][19] 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 Africa where malaria is epidemic.[20] People of African descent have evolved to have higher rates of the mutant HBB because the heterozygous individuals have a misshaped red blood cell that prevent attacks from malarial parasites. Thus, HBB mutants are the sources of positive selection in these regions and are important for their long-term survival.[2][21] Such selection markers are important for tracing human ancestry and diversification from Africa.[22]

See also

References

  1. 1 2 "Entrez Gene: HBB hemoglobin, beta".
  2. 1 2 Sabeti, Pardis C (2008). "Natural selection: uncovering mechanisms of evolutionary adaptation to infectious disease". Nature Education 1 (1): 13.
  3. 1 2 Kwiatkowski DP (2005). "How malaria has affected the human genome and what human genetics can teach us about malaria". The American Journal of Human Genetics 77 (2): 171–192. doi:10.1086/432519. PMC 1224522. PMID 16001361.
  4. ↑ Levings PP, Bungert J (2002). "The human beta-globin locus control region". Eur. J. Biochem. 269 (6): 1589–99. doi:10.1046/j.1432-1327.2002.02797.x. PMID 11895428.
  5. ↑ 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 (2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell 122 (6): 957–968. doi:10.1016/j.cell.2005.08.029. PMID 16169070.
  6. ↑ Shaanan B (1983). "Structure of human oxyhaemoglobin at 2.1 A resolution". J. Mol. Biol. (ENGLAND) 171 (1): 31–59. doi:10.1016/S0022-2836(83)80313-1. ISSN 0022-2836. PMID 6644819.
  7. ↑ "Hemoglobin Synthesis". harvard.edu. Harvard University. 2002. Retrieved 18 November 2014.
  8. ↑ Muncie HL, Campbell J (2009). "Alpha and beta thalassemia". American Family Physician 80 (4): 339–44. PMID 19678601.
  9. ↑ "Beta thalassemia". Genetics Home Reference. U.S. National Library of Medicine. 11 November 2014. Retrieved 18 November 2014.
  10. ↑ Valenti L, Canavesi E, Galmozzi E, Dongiovanni P, Rametta R, Maggioni P, Maggioni M, Fracanzani AL, Fargion S (2010). "Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease". Journal of Hepatology 53 (5): 927–933. doi:10.1016/j.jhep.2010.05.023. PMID 20739079.
  11. ↑ Piel FB, Howes RE, Patil AP, Nyangiri OA, Gething PW, Bhatt S, Williams TN, Weatherall DJ, Hay SI (2013). "The distribution of haemoglobin C and its prevalence in newborns in Africa". Scientific Reports 3 (1671). doi:10.1038/srep01671. PMC 3628164. PMID 23591685.
  12. ↑ 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 (2001). "Haemoglobin C protects against clinical Plasmodium falciparum malaria". Nature 414 (6861): 305–308. doi:10.1038/35104556. PMID 11713529.
  13. ↑ Verra F, Bancone G, Avellino P, Blot I, Simporé J, Modiano D (2007). "Haemoglobin C and S in natural selection against Plasmodium falciparum malaria: a plethora or a single shared adaptive mechanism?". Parassitologia 49 (4): 209–13. PMID 18689228.
  14. ↑ Olivieri NF, Pakbaz Z, Vichinsky E (2011). "Hb E/beta-thalassaemia: a common & clinically diverse disorder". The Indian Journal of Medical Research 134 (4): 522–531. PMC 3237252. PMID 22089616.
  15. ↑ Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J, Looareesuwan S, White N (2002). "Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria". Blood 100 (4): 1172–1176. PMID 12149194.
  16. ↑ Thom CS, Dickson CF, Gell DA, Weiss MJ (2013). "Hemoglobin variants: biochemical properties and clinical correlates". Cold Spring Harb Perspect Med 3 (3): a011858. doi:10.1101/cshperspect.a011858. PMID 23388674.
  17. ↑ 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 (2012). "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". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
  18. ↑ Luzzatto L (2012). "Sickle cell anaemia and malaria". Mediterr J Hematol Infect Dis 4 (1): e2012065. doi:10.4084/MJHID.2012.065. PMC 3499995. PMID 23170194.
  19. ↑ Verra F, Mangano VD, Modiano D (2009). "Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies.". Parasite Immunology 31 (5): 234–53. doi:10.1111/j.1365-3024.2009.01106.x. PMID 19388945.
  20. ↑ Tishkoff SA, Williams SM (2002). "Genetic analysis of African populations: human evolution and complex disease.". Nature Reviews Genetics 3 (8): 611–21. doi:10.1038/nrg865. PMID 12154384.
  21. ↑ Excoffier L (2002). "Human demographic history: refining the recent African origin model". Current Opinion in Genetics & Development 12 (6): 675–682. doi:10.1016/S0959-437X(02)00350-7. PMID 12433581.
  22. ↑ Reed FA, Tishkoff SA (2006). "African human diversity, origins and migrations". Current Opinion in Genetics & Development 16 (6): 597–605. doi:10.1016/j.gde.2006.10.008. PMID 17056248.

Further reading

  • Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ (1989). "A review of the molecular genetics of the human alpha-globin gene cluster.". Blood 73 (5): 1081–104. PMID 2649166. 
  • Giardina B, Messana I, Scatena R, Castagnola M (1995). "The multiple functions of hemoglobin.". Crit. Rev. Biochem. Mol. Biol. 30 (3): 165–96. doi:10.3109/10409239509085142. PMID 7555018. 
  • Salzano AM, Carbone V, Pagano L, Buffardi S, De RC, Pucci P (2002). "Hb Vila Real [beta36(C2)Pro-->His] in Italy: characterization of the amino acid substitution and the DNA mutation.". Hemoglobin 26 (1): 21–31. doi:10.1081/HEM-120002937. PMID 11939509. 
  • Frischknecht H, Dutly F (2007). "A 65 bp duplication/insertion in exon II of the beta globin gene causing beta0-thalassemia.". Haematologica 92 (3): 423–4. doi:10.3324/haematol.10785. PMID 17339197. 
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