Hemoglobin Hopkins-2
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Hemoglobin Hopkins-2 (Hb Hop-2) is a mutation of the protein
hemoglobin 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 (erythrocyt ...
, which is responsible for the transportation of oxygen through the blood from the lungs to the musculature of the body in vertebrates. The specific mutation in Hemoglobin Hopkins-2 results in two abnormal α chains (human hemoglobin consist of 2 α and 2 β polypeptides usually termed chains). The mutation is the result of
histidine Histidine (symbol His or H) is an essential 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), a carboxylic acid group (which is in the d ...
112 being replaced with aspartic acid in the protein's polypeptide sequence. Additionally, within one of the mutated alpha chains, there are substitutes at 114 and 118, two points on the amino acid chain. This mutation can cause
sickle cell anemia 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 bl ...
. Following the initial discovery of hemoglobin, two researchers working at
Johns Hopkins Hospital The Johns Hopkins Hospital (JHH) is the teaching hospital and biomedical research facility of the Johns Hopkins School of Medicine, located in Baltimore, Maryland, U.S. It was founded in 1889 using money from a bequest of over $7 million (1873 m ...
in the mid-twentieth century, Ernest W. Smith and J.V. Torbert, discovered the Hopkins-2 mutation of hemoglobin. Work by Harvey A. Itano and Elizabeth A. Robinson in 1960 confirmed Smith's and Torbert's finding and emphasized the importance of the alpha loci in the mutation. Later in the twentieth century, Samuel Charache, another Hopkins affiliated scientist and doctor, studied the physiological impacts of the variant on health. His findings suggest that the variant plays no effect clinically.


History

In the mid-1900s, many factors prompted hemoglobin research in
Baltimore, Maryland Baltimore ( , locally: or ) is the List of municipalities in Maryland, most populous city in the U.S. state of Maryland, fourth most populous city in the Mid-Atlantic (United States), Mid-Atlantic, and List of United States cities by popula ...
and ultimately led to the discovery of Hemoglobin Hopkins-2. First, the development of new technology, including
x-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
and protein chemistry, that could be utilized in molecular biology studies catalyzed research. Furthermore, the large presence of thalassemia (Hb H), a disorder in which the alpha gene is dysfunctional, in Southeast Asia and southern China further concerned researchers as, if left untreated, the mutation could result in bone deformities, swelling of the spleen, slowed growth rate, or cardiac dysfunction. Additionally,
Max Perutz Max Ferdinand Perutz (19 May 1914 – 6 February 2002) was an Austrian-born British molecular biologist, who shared the 1962 Nobel Prize for Chemistry with John Kendrew, for their studies of the structures of haemoglobin and myoglobin. He went ...
's, a Cambridge researcher, discovery of hemoglobin's basic
tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may i ...
in 1962 catalyzed research in hematology. Vernon Ingram's research surrounding
sickle cell anemia 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 bl ...
in 1956 revealed that variants, or mutations, in hemoglobin's RNA resulted in the
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 b ...
. Ernest W. Smith and J.V. Norbert examined Ingram's discovery and, in 1958, they discovered the hemoglobin Hopkins-2 mutation. Smith and Torbert, research fellows working in Lockard Conley's Hematology Research Department at Johns Hopkins University, proved that recombination of non-allelic genes resulted in two variants of the gene that produced hemoglobin. Variants of the "normal" hemoglobin gene result in mutation in the hemoglobins produced. In other words, the researchers discovered two versions of
hemoglobin 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 (erythrocyt ...
: the b-Hop2and S variants. Smith's and Torbert's findings were confirmed and built upon by Harvey A. Itano and Elizabeth A. Robinson in 1960. In their paper, ''Genetic Control of the a- and B-Chains of Hemoglobin'', Itano and Robinson explained that both the alpha and beta loci are involved in the regulation of hemoglobin. The recombination of the alpha loci on the gene coding for hemoglobin results in a mutation of the hemoglobin protein. Researchers refer to this mutated protein as a Hopkins-2 variation of hemoglobin. Further research surrounding the Hopkins-2 genetic mutation was conducted by Johns Hopkins doctors, who remained engaged in research in the hematologic field despite a general change in focus away from hematology in the medical community. Prominent Hopkins researcher Samuel Charache was one of many scientists at Hopkins who investigated
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
and its components during the late twentieth century. Specifically, Charache is well known for his work with George Dover, another Hopkins researcher; together, they discovered a treatment option for
sickle cell anemia 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 bl ...
. However, Charache was also engaged in hemoglobin Hopkins-2 research. In his
Nature Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans are ...
article, titled ''Clinical Studies and Physiological Properties of Hopkins Hemoglobin-2,'' Charache announced his discoveries surrounding the hemoglobin variant. Charache focused on physical implications of the variant, rather than on genetics themselves. Ultimately, Charache asserts in his paper that the variant is not prominent
phenotypically In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
and plays an unnoticeable or no effect on human health.


Hemoglobin and hematology at Hopkins

Hematologic studies were prominent at Johns Hopkins Hospital prior to the discovery of the hemoglobin Hopkins-2 variant. After observing the cells under a
microscope A microscope () is a laboratory instrument used to examine objects that are too small to be seen by the naked eye. Microscopy is the science of investigating small objects and structures using a microscope. Microscopic means being invisi ...
, Sir William Osler connected the concept of dysfunctional platelets to the development of ulcerative endocarditis and
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...
. Osler's initial observations of platelets catalyzed the study of blood and hematology at Hopkins and in other research environments. Platelets were discovered independently by Max Schultze in 1865 and G. Bizzozero in 1882. Beginning in 1920, doctors at Johns Hopkins Hospital conducted research on
sickle cell anemia 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 bl ...
, or sickle cell disease. Although their conclusions surrounding the disease are outdated, Doctors Taliaferro and Huck discovered a
latent Latency or latent may refer to: Science and technology * Latent heat, energy released or absorbed, by a body or a thermodynamic system, during a constant-temperature process * Latent variable, a variable that is not directly observed but inferred ...
form of sickle cell anemia. Their study on sickle cell anemia was the first of many to occur at Hopkins. In 1940, Irving Sherman, a medical student at Johns Hopkins, correctly identified the
deoxygenation Deoxygenation is a chemical reaction involving the removal of oxygen atoms from a molecule. The term also refers to the removal of molecular oxygen (O2) from gases and solvents, a step in air-free technique and gas purifiers. As applied to orga ...
of hemoglobin in sickle cell patients after he noted
refraction In physics, refraction is the redirection of a wave as it passes from one medium to another. The redirection can be caused by the wave's change in speed or by a change in the medium. Refraction of light is the most commonly observed phenome ...
patterns characteristic of deoxygenation when light was passed through the protein. The deoxygenation of hemoglobin in sickle cell patients has severe implications on those who carry the mutation. The hemoglobin proteins, present in those with sickle cell disease, cannot carry oxygen to the organs and other tissues of the human body. This results in pain crises and the disease results in an abbreviated
life expectancy Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, current age, and other demographic factors like sex. The most commonly used measure is life expectancy at birth ...
of 40–60 years. Ernest W. Smith and Torbert were integral in the discovery of Hopkins Hemoglobin-2, in addition to many other hematologic mutations and conditions. The two scientists worked together at Hopkins to identify the N-Baltimore mutation of Hemoglobin in 1958. Also referred to as the Hopkins-I, Jenkins, N-Memphis, or Kenwood mutation, the N-Baltimore mutation is a point mutation in which a
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
codon is replaced with an adenosine codon. The N-Baltimore mutation is associated with the C and S mutations of hemoglobin. Smith conducted extensive research in conjunction with Locklard Conley, one of Smith's bosses at the time of the Hopkins Hemoglobin-2 variant discovery. Lockard Conley, commonly referred to as "Lock," was a Johns Hopkins undergraduate and Columbia trained doctor. In 1947, Conley became the first director of the Hematology Department at Hopkins and remained in the position for 33 years. While there, he studied blood-related diseases, such as blood coagulation and
sickle cell anemia 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 bl ...
, and invented machinery to analyze molecular species. Specifically, he and Smith created a device that allowed for the separation of hemoglobin variants from standard hemoglobin molecules. Conley's impact on hematology, therefore, was not only scientific discovery; but, also, technological discovery that allowed the hematologic field to expand. Conley remained a doctor and professor at
Johns Hopkins Hospital The Johns Hopkins Hospital (JHH) is the teaching hospital and biomedical research facility of the Johns Hopkins School of Medicine, located in Baltimore, Maryland, U.S. It was founded in 1889 using money from a bequest of over $7 million (1873 m ...
until his death in 2010. Although a significant amount of hematologic research was completed during the 1950s and 1960s, scientists questioned whether more research could be completed without the development of more advanced technology. Ultimately, this doubt resulted in fewer scientists pursuing research in hematology in the mid twentieth century. Despite the scarcity of researchers, new discoveries surrounding genetics and hemoglobin were made. However, research continued in major medical laboratories, like Hopkins. In the mid and late twentieth century, both doctors George J. Dover and Samuel Charache studied sickle cell anemia's pathology at Johns Hopkins Hospital. Together, they implemented treatment of the disease through the use of a cancer drug,
hydroxyurea Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and d ...
; the drug was successful in alleviating some of the painful spurts associated with
sickle cell anemia 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 bl ...
, in addition to
pulmonary The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...
symptoms associated with the disease. Dover, a pediatric hematologist and expert on
fetal hemoglobin Fetal hemoglobin, or foetal haemoglobin (also hemoglobin F, HbF, or α2γ2) is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream ...
, initiated the use of the protein as a way to treat sickle cell anemia in adults.


Medical implications

The Hopkins-2 variant of hemoglobin has an oxygen affinity within the body, meaning that there is an increase of oxygen spreading through the body due to the fact that Ho-2 carries a higher amount of oxygen.Huisman, Titus H. J, Marianne F. H. Carver, and Georgi Efremov. ''A Syllabus of Human Hemoglobin Variants (1996)''. Augusta, GA, USA: The Sickle Cell Anemia Foundation, 1996. Print. There is no red cell effect with Ho-2 compared to
Hemoglobin S 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 ...
, which changes the shape of the cell to become sickled. The Hopkins-2 variant of hemoglobin is not involved in forming sickle cells. There is a lack of phenotypic expression of Ho-2 in terms of sickle cell, so a person with sickle cell and hemoglobin Hopkins-2 would be asymptomatic.


Genetic basis

The Hopkins 2 variant of
hemoglobin 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 (erythrocyt ...
is the result of a mutation. Specifically, the mutated protein is composed of two alpha chains. The mutation for the Hopkins-2 variant of hemoglobin is located on the surface of the molecule. Within the Ho-2 variant, aspartic acid replaces
histidine Histidine (symbol His or H) is an essential 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), a carboxylic acid group (which is in the d ...
at position 112 on the alpha chain. Dr.
Max Perutz Max Ferdinand Perutz (19 May 1914 – 6 February 2002) was an Austrian-born British molecular biologist, who shared the 1962 Nobel Prize for Chemistry with John Kendrew, for their studies of the structures of haemoglobin and myoglobin. He went ...
examined the aspartic acid in alpha 112 claiming that the carboxyl group of the amino acid forms a hydrogen bond with phenolix hydroxyl, which in turn stabilizes the structure of the molecule and increases oxygen affinity. Ho-2 hemoglobin has high levels of oxygen, which replaces the lack of oxygen within red blood cells. Ho-2 is similar to
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 ...
, which is normal hemoglobin and also contains two α-chains. This provides an explanation as to how the Hopkins-2 variant of hemoglobin is related to the symptoms of
sickle cell 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 ...
. Hopkins-2 can also interact specifically with Hemoglobin S.
Hemoglobin S 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 ...
is the most common abnormal hemoglobin variant. Hemoglobin S is the variant that causes
sickle cell 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 ...
, which is a disorder in which red blood cells break down and become abnormally shaped. Hemoglobin S has two beta chains, whereas hemoglobin Hopkins-2 has two alpha chains. Hopkins-2 makes up 22% of hemolysates in single heterozygotes; therefore, there is the normal version of the gene in these patients. Hemolysates are the products of the destruction of red blood cells. Ho-2 also comprises 11% of hemolysates in ‘double’ heterozygotes, which are when the gene contains both Hopkins-2 and Hemoglobin S. There are currently multiple possible explanations as to how the Hemoglobin variant Hopkins-2 works. One explanation that scientists have come up with is that Ho-2 is created due to a point mutation causing the substitution of histidine by aspartic acid. The other explanation is that there is an unequal crossing over between two α genes which explains the replacement of histidine by aspartic acid. This then led a deletion occurring within the chromosome housing Ho-2. This deletion removes the region where the N-terminus is located in the major α-chain and where the c-terminus is located on the minor α-chain. Deletion of the N-terminus inactivates enzymes and halting their ability to cut chains at certain areas, which inevitably damages the chain.


Case studies

Case studies were completed on some patients who carried the Hemoglobin Hopkins-2 genetic mutation by Samuel Charache and others. Researchers concluded after completing the studies that many of carriers of the mutation were asymptomatic to sickle cell and were overall quite healthy. Any medical issues that occurred had no correlation to sickle cell. These studies occurred in the 1970s.


Fuller-Carr family

There were five carriers of Hemoglobin Hopkins 2 in the Fuller-Carr family and ten double heterozygotes of Ho-2 and Hemoglobin S. All the carriers were in good health and had normal hematology test results. Out of those carrying
hemoglobin S 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 Ho-2, none were
anemic Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
; but, a few of those studied displayed elevated reticulocyte counts. This is measured through a blood test that analyzes the speed of production of red blood cells by bone marrow and its release into the blood. There was no suggestion of symptomatic sickle cell anemia in the family.


Unknown child

There was a study on a three-year-old that was a carrier of the hemoglobin variant of Hopkins-2. The child had mild anemia and reticulocytosis, which is commonly seen in anemia.Steinberg, Martin H., et al. ''Disorders of hemoglobin: genetics, pathophysiology, and clinical management''. Cambridge University Press, 2009. There were, however, no sickled cells found in the blood and they had no symptoms relating to sickle cell. There was also a reduced mean corpuscular volume (MCV), which is the average volume of
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 ...
count.


References

{{Reflist Hemoglobins Disorders of globin and globulin proteins Mutation