![HBB location](https://upload.wikimedia.org/wikipedia/commons/0/07/HBB_location.png)
Hemoglobin subunit beta (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a
globin
The globins are a superfamily of heme-containing globular proteins, involved in binding and/or transporting oxygen. These proteins all incorporate the globin fold, a series of eight alpha helical segments. Two prominent members include myo ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
, coded for by the ''HBB'' gene, which along with alpha globin (
HBA), makes up the most common form of
haemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
in adult humans,
hemoglobin A
Hemoglobin A (HbA), also known as adult hemoglobin, hemoglobin A1 or α2β2, is the most common human hemoglobin tetramer, accounting for over 97% of the total red blood cell hemoglobin. Hemoglobin is an oxygen-binding protein, found in erythrocyte ...
(HbA).
It is 147 amino acids long and has a molecular weight of 15,867
Da. Normal adult human HbA is a
heterotetramer
A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer ca ...
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
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
and
beta thalassemia
Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cli ...
, as well as beneficial traits such as
genetic resistance to malaria
Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to ...
.
At least 50 disease-causing mutations in this gene have been discovered.
Gene locus
HBB protein is produced by the gene ''HBB'' which is located in the multigene locus of
β-globin locus on
chromosome 11
Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
, specifically on the short arm position 15.4.
Expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
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.
The normal allelic variant is 1600
base pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s (bp) long and contains three
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s. The order of the genes in the beta-globin cluster is 5' -
epsilon
Epsilon (, ; uppercase , lowercase or lunate ; el, έψιλον) is the fifth letter of the Greek alphabet, corresponding phonetically to a mid front unrounded vowel or . In the system of Greek numerals it also has the value five. It was der ...
–
gamma-G –
gamma-A –
delta
Delta commonly refers to:
* Delta (letter) (Δ or δ), a letter of the Greek alphabet
* River delta, at a river mouth
* D ( NATO phonetic alphabet: "Delta")
* Delta Air Lines, US
* Delta variant of SARS-CoV-2 that causes COVID-19
Delta may also ...
– beta - 3'.
Interactions
HBB
interacts with
Hemoglobin, alpha 1
Hemoglobin subunit alpha, Hemoglobin, alpha 1, is a hemoglobin protein that in humans is encoded by the ''HBA1'' gene.
Gene
The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseu ...
(HBA1) to form haemoglobin A, the major haemoglobin in adult humans.
The interaction is two-fold. First, one HBB and one HBA1 combine, non-covalently, to form a dimer. Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemolglobin.
Associated genetic disorders
Beta thalassemia
Beta thalassemia
Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cli ...
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. Beta thalassemia major can be treated by lifelong
blood transfusions
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mod ...
or
bone marrow transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produc ...
.
According to a recent study, the stop gain mutation Gln40stop in ''HBB'' gene is a common cause of
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
Beta- thalassemia in
Sardinian people
The Sardinians, or Sards ( sc, Sardos or ; Italian and Sassarese: ''Sardi''; Gallurese: ''Saldi''), are a Romance language-speaking ethnic group native to Sardinia, from which the western Mediterranean island and autonomous region of Italy deri ...
(almost exclusive in Sardinia). Carriers of this mutation show an enhanced red blood cell count. As a curiosity, the same mutation was also associated to a decrease in serum
LDL
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
levels in carriers, so the authors suggest that is due to the need of
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
to regenerate cell membranes.
Sickle cell disease
More than a thousand naturally occurring ''HBB'' variants have been discovered. The most common is HbS, which causes
sickle cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
. HbS is produced by a
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
in ''HBB'' in which the
codon
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
GAG is replaced by GTG. This results in the replacement of hydrophilic amino acid
glutamic acid
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
with the hydrophobic amino acid
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
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 hemoglobin molecule's beta chain. This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s in the
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
(''HbS/HbS'') condition. The homozygous allele has become one of the deadliest genetic factors, whereas people heterozygous for the mutant allele (''HbS/HbA'') are resistant to
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
and develop minimal effects of the anaemia.
Haemoglobin C
Sickle cell disease is closely related to another mutant haemoglobin called
haemoglobin C
Hemoglobin C (abbreviated as HbC) is an abnormal hemoglobin in which glutamic acid residue at the 6th position of the HBB, β-globin chain is replaced with a lysine residue due to a point mutation in the ''Human β-globin locus, HBB'' gene. People ...
(HbC), because they can be inherited together. HbC mutation is at the same position in HbS, but glutamic acid is replaced by
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
(β6Glu→Lys). The mutation is particularly prevalent in West African populations. HbC provides near full protection against ''
Plasmodium falciparum
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
''in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals. This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions.
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). 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.
Human evolution
Malaria due to ''Plasmodium falciparum'' is a major selective factor in
human evolution
Human evolution is the evolutionary process within the history of primates that led to the emergence of ''Homo sapiens'' as a distinct species of the hominid family, which includes the great apes. This process involved the gradual development of ...
.
[ 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. 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.][ Such selection markers are important for tracing human ancestry and diversification from Africa.]
See also
* Hemoglobin subunit alpha
Hemoglobin subunit alpha, Hemoglobin, alpha 1, is a hemoglobin protein that in humans is encoded by the ''HBA1'' gene.
Gene
The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pse ...
* Human β-globin locus The human β-globin locus is composed of five genes located on a short region of chromosome 11, responsible for the creation of the beta parts (roughly half) of the oxygen transport protein Haemoglobin. This locus contains not only the beta globin ...
References
Further reading
*
*
*
*
External links
*
*
{{Hemeproteins
Hemoglobins