Hemoglobin D
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Hemoglobin D (HbD) is a variant of hemoglobin, a protein complex that makes up
red blood cells Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
. Based on the locations of the original identification, it has been known by several names such as hemoglobin D-Los Angeles, hemoglobin D-Punjab, D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago. Hemoglobin D-Los Angeles was the first type identified by Harvey Itano in 1951, and was subsequently discovered that hemoglobin D-Punjab is the most abundant type that is common in the
Sikhs Sikhs (singular Sikh: or ; , ) are an ethnoreligious group who adhere to Sikhism, a religion that originated in the late 15th century in the Punjab region of the Indian subcontinent, based on the revelation of Guru Nanak. The term ''Sikh'' ...
of Punjab (of both Pakistan and India) and of Gujarat. Unlike normal adult human hemoglobin ( HbA) which has
glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) 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 ...
at its 121 amino acid position, it has
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
instead. The single amino acid substitution can cause various
blood diseases :''This is an incomplete list, which may never be able to satisfy certain standards for completion.'' There are many conditions of or affecting the human hematologic system—the biological system that includes plasma, platelets, leukocytes, an ...
, from fatal genetic anemia to mild
hemolytic anemia Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
, an abnormal destruction of red blood cells. Depending on the type of genetic inheritance, it can produce four different conditions: heterozygous (inherited in only one of the chromosome 11) HbD trait, HbD-
thalassemia Thalassemias are a group of Genetic disorder, inherited blood disorders that manifest as the production of reduced hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe, including death. Often there is mild to ...
, HbS-D ( sickle cell) disease, and, very rarely, homozygous (inherited in both chromosome 11) HbD disease. It is the fourth hemoglobin type discovered after HbA, HbC and HbS; the third hemoglobin variant identified after HbC and HbS; and the fourth most common hemoglobin variant after HbC, HbS, and HbO.


History

Hemoglobin was discovered as some sort of crystal formed from earthworm body fluid and animal blood by German biochemist Friedrich Ludwig Hünefeld at
Leipzig University Leipzig University (), in Leipzig in Saxony, Germany, is one of the world's oldest universities and the second-oldest university (by consecutive years of existence) in Germany. The university was founded on 2 December 1409 by Frederick I, Electo ...
in 1840. When the protein nature was established another German
Felix Hoppe-Seyler Ernst Felix Immanuel Hoppe-Seyler (''né'' Felix Hoppe; 26 December 1825 – 10 August 1895) was a German physiologist and chemist, and the principal founder of the disciplines of biochemistry and molecular biology. He had discovered Yeast nuclei ...
gave the name hemoglobin (literally "blood protein") in 1864. Its role as an oxygen transporter was later established. While studying
sickle cell disease Sickle cell disease (SCD), also simply called sickle cell, is a group of inherited Hemoglobinopathy, haemoglobin-related blood disorders. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the ...
,
Linus Pauling Linus Carl Pauling ( ; February 28, 1901August 19, 1994) was an American chemist and peace activist. He published more than 1,200 papers and books, of which about 850 dealt with scientific topics. ''New Scientist'' called him one of the 20 gre ...
and Harvey Itano at the
California Institute of Technology The California Institute of Technology (branded as Caltech) is a private research university in Pasadena, California, United States. The university is responsible for many modern scientific advancements and is among a small group of institutes ...
discovered in 1949 that the disease was due to abnormal hemoglobin, later called hemoglobin S (HbS). In 1950, Itano and James V. Neel discovered a slightly different case in which individuals had sickled red blood cells but not anemia. The hemoglobin was named hemoglobin III, but later known as hemoglobin C (HbC). In 1934, Jean V. Cooke and J. Keller Mack, pediatricians at St. Louis, USA, reported a case of white American family which had some member suffering from sickle cell anemia. Of six siblings, two children had anemia, while others, including their parents, were healthy. Blood tests indicated the two children had sickled red blood cells, but with uncharacteristically slow process of sickling. The father, who had no disease, was found to have sickled re blood cells. With the new techniques for identifying different hemoglobin, Itano investigated the family and found that like their father, three other children had abnormal hemoglobin but without the disease or sickled cells; their hemoglobin giving same mobility (in
electrophoresis Electrophoresis is the motion of charged dispersed particles or dissolved charged molecules relative to a fluid under the influence of a spatially uniform electric field. As a rule, these are zwitterions with a positive or negative net ch ...
) and but different solubility as sickled cells. He recorded in 1951:
The resent report deals with the identification of still another form of human hemoglobin in five members of a family in which the genetic picture is not typical of sickle cell anemia, although two of the members have in the past been diagnosed as having sickle cell anemia. An earlier study of this family disclosed that the two anemic children and the father, who was not anemic, had sickling erythrocytes while the mother, two sisters and two brothers of the anemic children had non-sickling erythrocytes and were not anemic.
In the paper published in the ''
Proceedings of the National Academy of Sciences of the United States of America ''Proceedings of the National Academy of Sciences of the United States of America'' (often abbreviated ''PNAS'' or ''PNAS USA'') is a peer-reviewed multidisciplinary scientific journal. It is the official journal of the National Academy of Scie ...
'', Itano presented the need to have naming convention for the different types of hemoglobin, and introduced the alphabet-coding system such as hemoglobin ''a'' (for normal adult type), ''b'' (sickle cell type), ''c'' (sickle cell-associated type) and ''d'' (for the novel type); as he explained:
In order to facilitate the discussion in the present paper and to avoid confusion in future works, it seems desirable at this time to establish a system of symbols for identifying the various forms of adult human hemoglobin... normal hemoglobin, sickle cell hemoglobin, the abnormal hemoglobin reported by Itano and Neel, and the abnormal hemoglobin reported in the present paper will be designated adult human hemoglobins a, b, c and d, respectively, more briefly as hemoglobins a, b, c and d.
It was the discovery of hemoglobin D and creation of hemoglobin naming system. In 1953, Amoz Immanuel Chernoff at the Washington University School of Medicine, St. Louis, introduced the capitalised-letter designation such as A (for normal adult type), C (second abnormal type), D (third abnormal type), S (sickle cell type) and F (fetal form). Although the nomeclature system became a convention, hemoglobin D, in particular, became known by various names, generally based on their origin of identification; like hemoglobin D-Los Angeles for the first discovered, hemoglobin D-Punjab, D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago. By 1961, it was known that the structural difference of HbD from HbA was in the β-chain. Around the same time, Corrado Baglioni of Massachusetts Institute of Technology identified the exact abnormality that substitution of glutamic acid with glutamine at position 121 in the β-chain was the basis of HbD, the findings which he reported in 1962.


Structure

Hemoglobin D has the basic structure and composition of normal adult hemoglobin. It is a globular protein containing
prosthetic In medicine, a prosthesis (: prostheses; from ), or a prosthetic implant, is an artificial device that replaces a missing body part, which may be lost through physical trauma, disease, or a condition present at birth (Congenital, congenital disord ...
(non-protein) group called heme. There are four individual peptide chains, namely two α- and two β-subunits, each made of 141 and 146 amino acid residues, respectively. One heme is associated with each chain and responsible for binding free oxygen in the blood. A single HbD is therefore a
tetramer A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...
(containing four molecules), denoted as α2β2. Each subunit has a molecular weight of about 16,000 Da ( daltons), making the tetramer about 64,000 Da (64,458 g/mol) in size. HbD is different from HbA only on the β-subunit where the amino acid glutamic acid at 121 position is replaced with glutamine (α2β2121Glu→Gln). It has the same chemical characteristic as HbS (a hemoglobin of sickle cell trait), with one fewer negative charge at an alkaline pH than HbA. However, unlike HbS, it does not produce sickled RBC on its own under low level of oxygen.


Genetics and diseases

Hemoglobin D is synthesised due to mutation in ''HBB'', the gene that produces β-subunits of hemoglobin and is present on human chromosome 11. A point mutation in the first base of the 121 codon that normally has GAA sequence for normal hemoglobin is changed to CAA. GAA codes for glutamic acid, while CAA for glutamine. This gene mutation makes HbD, which can further give rise to several genetic and disease conditions. The specific mutations can occur at different sites of the gene. According to the Globin Gene Server database, there are other types of HbD such as HbD-Agri (''HBB'':c.29C→A;364G→C), HbD-Bushman (''HBB'':c.49G→C), HbD-Ouled Rabah (''HBB'':c.60C→A or 60C→G), HbD-Iran (''HBB'':c.67G→C), HbD-Granada (''HBB'':c.68A→T), HbD-Ibadan (''HBB'':c.263C→A) and HbD-Neath (''HBB'':c.365A→C). Depending on the nature of inheritance of HbD mutation there are four conditions, some of which can be deadly diseases: # Heterozygous HbD/HbA trait, which does not affect the individuals. # Heterozygous HbD-thalassemia, which causes the symptoms of thalassemia generally with mild anemia. # Heterozygous HbS-D, which gives rise to sickle cell anemia, but generally milder and slower symptoms. # Homozygous HbD/HbD, which is the rarest form, but is associated with HbD disease.


Effects and symptoms

Hemoglobin in combination with normal hemoglobin (heterozygous HBD/HbA) is asymptomatic, causing no effects. Individuals have normal hemoglobin level and their red blood cells are normal spherical structure. Homozygous HbD/HbD causes mild hemolytic anemia and chronic non-progressive
splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulat ...
(enlargement of
spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...
). Heterozygous HbD/HbS causes sickle cell anemia. However, most cases of the disease are milder than the usual HbS/HbS conditions. The most serious complication noted is stroke. HbD-thalassemia causes microcytic anemia which is generally milder that in typical thalassemia.


Diagnosis

As hemoglobin can be inherited in several conditions, no single diagnostic test can confirm the specific protein completely. Electrophoresis is one of the most commonly used and requires sequential identification with other hemoglobins. All hemoglobins can be separated in cellulose acetate at pH 8.6 and in agarose gel at pH 6.2. In alkaline medium of cellulose acetate, HbD moves slower and can be identified at shorter distance than HbA, but it migrates exactly as HbS. It can be differentiated from HbS in acidic agarose gel in which it moves faster and farther than HbS, but at the same level with HbA.
High-performance liquid chromatography High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify specific components in mixtures. The mixtures can origin ...
(HPLC) can directly detect the protein, but its specific identification of HbD from other hemoglobins can be inconclusive. HPLC coupled with
mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...
(HPLC-ESI-MS/MS) can accurately detect the protein but the procedure is costly and time consuming. Genetic screening can be done with
polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to make millions to billions of copies of a specific DNA sample rapidly, allowing scientists to amplify a very small sample of DNA (or a part of it) sufficiently to enable detailed st ...
that can identify HbS from other hemoglobin variants.


Management

Hemoglobin D conditions such as homozygous and HbD/HbA heterozygous do not require medical intervention. HbD/HbS and HbD-thalassemia conditions are managed like the typical cases of sickle cell anemia and thalassemia. In case of sickle cell anemia, daily treatment with
penicillin Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...
recommended up to five years of age. Dietary supplementation of
folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
is recommended by the
WHO The World Health Organization (WHO) is a specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Geneva, Switzerland, and has 6 regional offices and 15 ...
. In 2019,
Crizanlizumab Crizanlizumab, sold under the brand name Adakveo among others, is a monoclonal antibody medication that binds to P-selectin. It is a medication used to reduce the frequency of vaso-occlusive crisis in people aged 16 years and older who have sick ...
, a monoclonal antibody was approved by the United States FDA for reducing the frequency of blood vessel blockage in 16 years and older individuals. For thalassemia, regular lifelong
blood transfusion Blood transfusion is the process of transferring blood products into a person's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used ...
s is the usual treatment. Bone marrow transplants can be curative for some children. Medications like
deferoxamine Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an ...
, deferiprone and luspatercept.
Gene therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...
, exagamglogene autotemcel is approved for medical use in the United Kingdom since November 2023.


Prevalence

Hemoglobin D is most abundant among Sikhs, with occurrence of 2% in Punjab and 1% in Gujarat. It is also found in small number of individuals among Africans, Americans and Europeans who usually had close ethnicity with Indians in the past. It is below 2% among African-Americans. Combination with β-thalassemia and HbS are known in south and east India; the first resulting in thalassemia and the latter in sickle cell anemia. There is also high occurrence in China, with prevalence rate of 12.5% in
Chongqing ChongqingPostal Romanization, Previously romanized as Chungking ();. is a direct-administered municipality in Southwestern China. Chongqing is one of the four direct-administered municipalities under the State Council of the People's Republi ...
. It is sporadically recorded in some Turkish, Algerian, West African, Saudi Arabian, native American, English, and Irish population. Rare conditions like HbD/HbJ, HbD/ HbQ, and HbD/Hb Fontainebleau are also found in India. A rare case of HbS/HbD is reported from Pakistan in which individuals are diagnosed with bone infection (
osteomyelitis Osteomyelitis (OM) is the infectious inflammation of bone marrow. Symptoms may include pain in a specific bone with overlying redness, fever, and weakness. The feet, spine, and hips are the most commonly involved bones in adults. The cause is ...
). An isolated condition of HbD/HbC is recorded in US.


References


External links


Disease information in Encyclopædia Britannica

Fact sheet
{{Medical resources, DiseasesDB=29718, ICD10={{ICD10, D, 58, 2, d, 55, ICD9={{ICD9, 282.7, ICDO=, OMIM=, MedlinePlus=, eMedicineSubj=, eMedicineTopic=, MeshID=C032001 Hemoglobins Respiratory physiology Blood disorders Genetic diseases and disorders