Anemia and Your Genes
Many people think of anemia as something that happens because of outside factors, like a poor diet, but in reality several types of anemia are related to glitches in genes, says Christal Murray, MD, a hematologist with Scott and White Hospital in Round Rock, Texas. “Some people inherit genes that, one way or another, cause problems with the blood,” Dr. Murray says.
Among the types of anemia that can be inherited are:
- Sickle-cell anemia. People with sickle-cell anemia have a gene that causes the blood protein hemoglobin to form abnormally. As a result, red blood cells are produced in a sickle shape. “This can cause painful episodes called crises, and even strokes and heart attacks,” Murray says. People with sickle-cell anemia may also experience swelling in the hands and feet and a reduced ability to fight infection. Sickle-cell anemia is most common in African-Americans, Murray says, but it also sometimes affects people of Hispanic, Indian, and Mediterranean descent.
- Thalassemia. Thalassemia occurs when your body is unable to produce enough hemoglobin, which functions to carry oxygen throughout the body. This condition is also caused by faulty genes. People with mild thalassemia often experience nothing more than the typical symptoms of anemia, such as tiredness, while those with a moderate or severe form may have an enlarged spleen, slowed growth, bone problems, and jaundice. “There are certain types severe enough that a fetus can die before it’s even born,” Murray says. Alternatively, “thalassemia can be slight enough that some people don’t find out they have the condition until they’re 50 or 60 when they have a mild anemia.”
- Congenital pernicious anemia. This rare type of anemia results when a person is born with an inability to produce intrinsic factor, a protein in the stomach that helps the body absorb vitamin B12. Without vitamin B12, the body cannot make enough healthy red blood cells, causing you to become anemic. The lack of vitamin B12 can lead to other complications, like nerve damage, memory loss, and an enlarged liver. Like other forms of pernicious anemia, this condition is usually treated with vitamin B12 supplements, which may need to be taken for a lifetime.
- Fanconi anemia. This type of anemia stems from an inherited blood disorder that prevents the bone marrow from producing an adequate supply of new blood cells for the body. Besides having the classic signs of anemia, such as fatigue and dizziness, some people with Fanconi anemia are also at greater risk for infection because their bodies don’t produce enough white blood cells to fight germs. Some patients are also at greater risk for acute myeloid leukemia, a type of blood cancer, because their bone marrow makes a large number of immature white blood cells, preventing the production of normal blood cells.
- Hereditary spherocytosis. This disease, which is usually passed from parent to child through the genes, is characterized by abnormal red blood cells called spherocytes that are thin and fragile. These cells cannot change shape to pass through certain organs as normal red blood cells do, so they stay in the spleen longer, where they are eventually destroyed. The destruction of the red blood cells causes anemia. Most people with hereditary spherocytosis have only mild anemia, but stresses on the body from infection can cause jaundice and even a temporary halt in the bone marrow’s production of blood cells.
- Thrombotic thrombocytopenic purpura. Known as TTP for short, this anemia-causing condition results from a certain faulty blood-clotting enzyme, leading to the clumping of platelets, which are blood cells that help heal wounds. When platelets clump together, fewer platelets are circulating throughout the body, so people with TTP can experience prolonged bleeding internally, externally, or under the skin. “It can result in anemia by affecting red blood cells once they get out of the bone marrow, causing breakages of those red blood cells in the blood,” Murray says. This is known as hemolytic anemia. TTP can be an acquired condition, meaning it develops later in life, but heritable forms of the disease also exist.
While there are steps many people can take to avoid anemia that is due to nutrient deficiencies or illnesses that can be cured, for those born with an anemia-based health condition, lifelong management is often a necessity.
Onset of CDA generally occurs in childhood or early adulthood, even if clinical signs can occasionally be observed in the neonatal period. Patients share chronic anemia of variable severity and jaundice, frequently associated with splenomegaly and/or hepatomegaly. Symptoms of anemia include fatigue, failure to thrive in infants, headache, dizziness, leg cramps, tachycardia and insomnia. Erythropoiesis is always dysfunctional, as revealed by cellular anomalies and erythroid hyperplasia. CDA I patients have a moderate macrocytic anemia with frequent splenomegaly and occasional hepatomegaly. Jaundice is intermittent and approximately 1/3 of patients have congenital malformations, mostly involving the limbs, but also the heart, kidneys or hip. The main complication is iron overload which can lead to organ damage. In CDA II, the most frequent type, anemia and/or jaundice is usually detected in children or young adults with splenomegaly. Liver iron overload and gallstones are frequent. CDA III is a very rare subtype characterized by mild hemolytic anemia and a predisposition to retinal angioid streaks, gammopathies and myeloma. CDA IV is characterized by the presence of a very large number of nucleated erythrocytes in the peripheral blood. Thrombocytopenia with CDA is characterized by dysmorphic erythrocytes and paucity of the platelets.
Iron-deficiency anemia happens because you don’t have enough of the mineral iron in your body. Your bone marrow needs iron to make hemoglobin, the part of the red blood cell that takes oxygen to your organs. Iron-deficiency anemia can be caused by:
- A diet without enough iron, especially in infants, children, teens, vegans, and vegetarians
- Certain drugs, foods, and caffeinated drinks
- Digestive conditions such as Crohn’s disease, or if you’ve had part of your stomach or small intestine removed
- Donating blood often
- Endurance training
- Pregnancy and breastfeeding using up iron in your body
- Your period
- A common cause is chronic slow bleed, usually from a Gastrointestinal source.
Sickle cell anemia is a disorder that, in the U.S., affects mainly African Americans and Hispanic Americans. Your red blood cells, which are usually round, become crescent-shaped because of a problem in your genes. They break down quickly, so oxygen doesn’t get to your organs, causing anemia. The crescent-shaped red blood cells can also get stuck in tiny blood vessels and cause pain.
Vitamin-deficiency anemia can happen when you aren’t getting enough vitamin B12 and folate. You need these two vitamins to make red blood cells. This kind of anemia can be caused by:
- Dietary deficiency: If you eat little or no meat, you might not get enough vitamin B12. If you overcook vegetables or don’t eat enough of them, you might not get enough folate.
- Megaloblastic anemia: When you don’t get enough vitamin B12, folate, or both
- Pernicious anemia: When your body doesn’t absorb enough vitamin B12
Other causes of vitamin deficiency include medications, alcohol abuse, and intestinal diseases such as tropical sprue.
Anemia associated with other chronic conditions usually happens when your body doesn’t have enough hormones to make red blood cells. Conditions that cause this type of anemia include:
- Advanced kidney disease
- Old age
- Long-term diseases, such as cancer, infection, lupus, diabetes, and rheumatoid arthritis
Anemia Caused by Destruction of Red Blood Cells
When red blood cells are fragile and can’t handle the stress of traveling through your body, they may burst, causing what’s called hemolytic anemia. You might have this condition at birth, or it could come later. Sometimes, the causes of hemolytic anemia are unclear, but they can include:
- An attack by your immune system, as with lupus. This can happen to anyone, even a baby still in the womb or a newborn. That’s called hemolytic disease of the newborn.
- Conditions that can be passed down through your genes, such as sickle cell anemia, thalassemia, and thrombotic thrombocytopenic purpura (TTP)
- Enlarged spleen. This can, in rare cases, trap red blood cells and destroy them too early.
- Something that puts strain on your body, such as infections, drugs, snake or spider venom, or certain foods
- Toxins from advanced liver or kidney disease
- Vascular grafts, prosthetic heart valves, tumors, severe burns, being around certain chemicals, severe hypertension, and clotting disorders
NIH researchers identify genetic cause of anemia disorder
NIH researchers identify genetic cause of anemia disorder
DNA barrier element implicated in human disease for the first time
Healthy red blood cells, left, are disk shaped and transport oxygen through narrow blood vessels. Red blood cells with deficient amkyrin have rigid spherical membrane walls, preventing passage through smaller blood vessels.
One of the most common types of familial anemia, hereditary spherocytosis (HS), is caused by a defect in a gene’s barrier insulator, a DNA element that keeps a gene’s switch in the ‘on’ position. A team led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), and Yale University School of Medicine, report on their findings in the early online issue of the Nov. 22, 2010, Journal of Clinical Investigation, marking the first time that a human disease is known to be caused by a defect in this otherwise poorly understood element in the genome.
HS affects 1 in 2,000 individuals of Northern European ancestry and is characterized by fatigue, anemia, enlargement of the spleen and sometimes jaundice. In this study, the researchers investigated a specific mutation in the non-coding region of the ankyrin-1 (ANK1) gene, the gene most commonly mutated in HS, and sought to determine whether the mutation was responsible for the ankyrin deficiency in patients with the disorder.
“Our study provides novel understanding of barrier insulator structure and function along with the particular role of this mechanism in a human disorder,” said senior author David Bodine, Ph.D., NHGRI senior investigator and chief of the Genetics and Molecular Biology Branch. “Barrier insulators are not well understood, but what we are learning is fundamental to gene regulation.”
Barrier insulators are stretches of DNA that reside outside the coding region of the genome and their associate binding proteins. Unlike genes, they do not code for human proteins or carry hereditary traits, but are among the complement of DNA elements that play a role in turning genes on and off. Barrier insulators create a barrier to help keep genes ‘on’ in the appropriate cell type.
People contain a vast number of cell types, all differing in their structure and function. All cell nuclei within an individual contain the same set of genes, some of which may or may not be switched on by regulatory elements also written in DNA code. These include enhancers, silencers and barrier insulators to name but a few. The genes that are turned on, or expressed, in the early phase of red blood cells (fully developed red blood cells do not contain nuclei) are different from those that form a skin or muscle cell.
ANK1 produces a protein necessary for the stability of the red cell membrane. The barrier insulator defect that causes HS was detected in DNA adjacent to the ANK1 promoter, the region just before the gene in its sequence that controls RNA production. Mutations in the barrier insulator lead to silencing of ANK1 and a deficiency of ankyrin protein in the cells. Ankyrin deficiency in red blood cells causes them to become spherically shaped rather than donut shaped and their cell membranes to lose the ability to mold and flex on their way through the tiny blood vessels that branch out to bring oxygen to tissues throughout the body.
The research team used a variety of approaches to demonstrate that this barrier insulator causes the disorder, including studies that showed a loss of barrier-associated proteins at the mutant ankyrin promoter and the use of transgenic mice to demonstrate that the barrier region could function independently of the ANK1 itself.
“Many studies have identified noncoding regions of the genome that are associated with specific diseases, but the role of those sequences in disease has not been demonstrated,” said the study’s lead author Patrick Gallagher, M.D., Yale University professor of pediatrics and genetics. Bodine added, “I believe our study is the first of many studies that will show that mutations in barrier insulator elements are responsible for numerous inherited and acquired diseases, including cancers.”
In addition to NHGRI, the study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute.
Last Updated: February 28, 2012
A Genetic Cause For Iron Deficiency
Iron deficiency is the most common nutritional deficiency and the leading cause of anemia in the United States.* Most cases are easily reversed with oral iron supplements, but over the years, Mark Fleming, MD, DPhil, interim Pathologist-in-Chief at Children’s Hospital Boston, and pediatric hematologist Nancy Andrews, MD, PhD, formerly of Children’s and now Dean of Duke University School of Medicine, had been referred a number of children with iron deficiency anemia who didn’t respond to oral supplements, and only poorly to intravenous iron.
The cause of their condition — termed iron-refractory iron-deficiency anemia (IRIDA) –was a mystery. The children all had good diets, and none had any condition that might interfere with iron absorption or cause chronic blood loss, the most common causes of iron deficiency. All had evidence of anemia from a very early age, and many also had siblings with iron deficiency anemia. Seeing reports of several similarly afflicted families in the medical literature, Fleming and Andrews were convinced that genetics was a factor.
“After nearly 15 years, we finally had enough families that we could begin to think about positionally cloning the gene for the disorder,” says Fleming.
Fleming and Andrews, experts in iron metabolism, and their colleagues Karin Finberg, MD, PhD, and Matthew Heeney, MD, studied five extended families with more than one chronically iron-deficient member. They found a variety of mutations in a gene called TMPRSS6 (the acronym stands for transmembrane serine protease S6) in all of these families, as well as several patients without a family history of the disorder.
Although IRIDA is quite rare, the authors believe it might be the extreme end of a broad continuum of disease, since TMPRSS6 mutations varied widely in the five families and caused different degrees of iron deficiency and anemia.
“Our observations suggest that more common forms of iron deficiency anemia may have a genetic component,” says Andrews.
All patients in the study apparently had recessive mutations, since their parents did not have iron deficiency anemia. The investigators now want to determine whether people with just a single abnormal copy of TMPRSS6 have subtler alterations in iron absorption that might not otherwise have come to the attention of a hematologist.
Although the mechanism is still unknown, deficiency of the TMPRSS6 protein causes the body to produce too much hepcidin, a hormone that inhibits iron absorption by the intestine. Normally, hepcidin is produced to protect the body against iron overload — but patients with IRIDA make large amounts of hepcidin even though they are iron deficient. “People with this disorder make too much hepcidin, putting the brakes on iron absorption inappropriately,” Fleming says.
In addition, patients with TMPRSS6 mutations cannot make new red blood cells efficiently because the iron needed to make them comes from macrophages, and hepcidin causes macrophages to hold on to iron. This explains the patients’ poor response to intravenous iron — the iron is trapped in macrophages and cannot be used for red blood cell production.
The fact that TMPRSS6 regulates hepcidin may open up new avenues for therapy, the researchers say. For example, blocking TMPRSS6 may help patients with iron overload disorders make more hepcidin in order to limit intestinal iron absorption. Conversely, stimulating TMPRSS6 may have therapeutic benefit in certain patients with anemia, particularly those in which hepcidin is overproduced.
The finding was published online by the journal Nature Genetics on April 13. The study was supported by the National Institutes of Health.
*Centers for Disease Control and Prevention. Iron deficiency — United States, 1999–2000. MMWR 2002;51:897–899.
Year : 2019 | Volume : 6 | Issue : 2 | Page : 57-61
A review on iron-refractory iron-deficiency anemia
Sangeetha Thangavelu1, T Varsha2, Vignesh Mariappan3, Vijaya Anand Arumugam2, Preethi Basavaraju2
1 Department of Human Genetics and Molecular Biology, Medical Genetics and Epigenetics Laboratory, Bharathiar University, Coimbatore, Tamil Nadu, India
2 Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
3 Central Inter-Disciplinary Research Facility (CIDRF), Sri Balaji Vidyapeeth University, Puducherry, India
|Date of Submission||06-Mar-2019|
|Date of Acceptance||14-Apr-2019|
|Date of Web Publication||23-Jul-2019|
Ms. Sangeetha Thangavelu
Department of Human Genetics and Molecular Biology, Medical Genetics and Epigenetics Laboratory, Bharathiar University, Coimbatore – 641 046, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Anemia is a common and predominant blood disorder globally, in which the level of hemoglobin or healthy red blood cells are abnormally lower. The most common type of anemia is iron-deficiency anemia (IDA), and the treatment is iron supplementation to the individuals. In some conditions, the iron supplementation does not alter the hemoglobin range, which means the iron given is not taken up by the body of the individual. This condition is found to be iron-refractory IDA (IRIDA). It is the genetic condition, in which the hepcidin, an iron regulatory hormone expression is altered. IRIDA is a rare genetic disorder, which is autosomal recessive in inheritance pattern. Hepcidin alteration blocks the iron absorption, which in turn causes anemic condition. The transmembrane protease serine 6 (TMPRSS6) gene is involved in negative regulation of hepcidin along with the encoding of matriptase-2 enzyme, which is crucial for iron balance in the human body. Matriptase-2 regulates the iron homeostasis by balancing the hepcidin hormone. The genetic polymorphisms in the TMPRSS6 gene result in this a rare type of anemic condition. Therefore, this review particularly focuses on the IRIDA and TMPRSS6 gene, hepcidin, and matriptase-2 enzyme. The review on IRIDA is being found to be important since the clear metabolism of hepcidin and matriptase-2 in iron metabolism are still unclear.
Keywords: Anemia, Hemojuvelin, Hepcidin, Iron-refractory iron-deficiency anemia, Matriptase-2, Transmembrane protease serine 6
How to cite this article:
Thangavelu S, Varsha T, Mariappan V, Arumugam VA, Basavaraju P. A review on iron-refractory iron-deficiency anemia. J Health Res Rev 2019;6:57-61
Iron is important for biological functions such as respiration, energy synthesis, and cell division. In our body, absorption of iron is limited to about 1–2 mg/day, but our body requires about 25 mg/day. It is provided by macrophages through recycling that phagocytose aged red blood cells (RBC). The iron absorption as well as phagocytosis of RBC is regulated by a specific hormone called hepcidin. It maintains total body iron within normal levels, avoiding both iron deficiency and excess. Iron-refractory iron-deficiency anemia (IRIDA) is a rare genetic condition, in which the iron absorption is totally absent as well as the body refuses to respond to the supplemented iron through medications. The prevalence of IRIDA is very less such that it is <1 in 1,00,000 people worldwide. And hence, the literature available for IRIDA in interconnection with transmembrane protease serine 6 (TMPRSS6) gene and hepcidin is very limited, and with the available evidence, this review highlights IRIDA, hepcidin role, and the genetic polymorphisms in the TMPRSS6 gene causing IRIDA.
|Need of the Review|
The literature, which has been analyzed for anemia followed by IRIDA in link with TMPRSS6 gene has been found to be constructive. This review has been mainly produced on the aim of giving a clear idea on the link of IRIDA with iron metabolism, hepcidin, and matriptase-2 on the genetic basis. The present literature search for IRIDA as a part of framed hypothesis has been carried out in the PubMed, Scopus, Web of Sciences, and SCI indexed journals, which is limited to humans and keywords such as hepcidin, anemia, hemojuvelin, matriptase-2, and TMPRSS6. In the preliminary stage, the basis of the study relevant to the title was identified. The abstracts were examined for the inclusion of this review.
Anemia has been considered global disorder with complex causes and many associated factors. Even though it is found to be associated with many factors, the major cause is deficiency of iron. The normal production and differentiation of RBC need number of essential nutrients including iron, vitamin B12, and folate. The deficiency in any of the above nutrient will result in decreased synthesis of RBC. Hemoglobin is the iron-containing metalloprotein of RBC, involved in the oxygen transport throughout the body. The improper RBC synthesis causes reduced hemoglobin range resulting in the anemic condition.
The World Health Organization has defined anemia is the condition, in which the hemoglobin level is <12 g/dL in women and 13.5 g/dL in men, whereas in case of newborns, hemoglobin level would be <14 g/dL and in infants 9.5 g/dL., It is a critical health issue worldwide. It majorly affects pregnant women and children. There are currently more than 400 types of anemia identified. Roughly, one-third of the world population is affected by anemia. Approximately, 164 million people are affected worldwide, but only four studies have been reported on the incidence levels.
Iron deficiency anemia (IDA) is the common problem worldwide, which is having the cause typically attributed to acquired improper diet and/or chronic blood loss. Lower iron absorption by the intestine, deficiency in dietary iron intake, increased iron requirements, and iron loss due to bleeding are the major causes of IDA. Iron loss during menstruation is the most common cause of IDA in women. Autoimmune atrophic gastritis and infection with Helicobacter pylori can also cause IDA by decreasing the iron absorption in intestines. In addition to these common causes, IRIDA may be caused due to germline mutations of TMPRSS6. Homozygosity for TMPRSS6 rs855791 C genotype has an active part in protection in women at reproductive age, against IDA, especially in those with menorrhagia.TF, TFR2, and TMPRSS6 polymorphisms are mainly associated with decreased iron levels, but only mutations in TMPRSS6 are genetic risk factors for iron deficiency and IDA.
|Iron-Refractory Iron-Deficiency Anemia|
IRIDA is a rare genetic disorder whose inheritance pattern is autosomal recessive. Autosomal recessive is a condition in which two copies of mutated alleles of the gene is required to cause a disease or disorder. It is usually characterized by hypochromic microcytic anemia, reduced transferrin saturation, and improper high levels of the iron-regulating hormone hepcidin. Variants in the TMPRSS6 gene which encodes the type II serine protease matriptase-2 enzyme, a regulator of negative feedback mechanism of hepcidin transcription causes this disease. The germline mutations of TMPRSS6 gene results in a disorder called IRIDA.TMPRSS6 mutations are distributed on the gene and that they completely or partially terminate hepcidin inhibition.
|Genetic Polymorphisms Causing Iron-Refractory Iron-Deficiency Anemia|
Transmembrane protease serine 6 and matriptase-2
Loss-of-function mutations in TMPRSS6 results in high hepcidin level that causes IRIDA and also severe anemia. Matriptase-2 is an enzyme which belongs to the type II transmembrane serine protease category, and the TMPRSS6 gene encodes this enzyme. Matriptase-2 was then established to be crucial in iron balance based on the characteristics of IRIDA observed in mice models and also in the human patients with mutations in TMPRSS6 gene. TMPRSS6 is expressed primarily in the liver, and its function is the negative regulation of hepcidin production. From the recent investigations, it has been clear that the function of matriptase-2 is regulation of hepcidin.,TMPRSS6 germline mutations in the humans resulted in IRIDA that is completely unsusceptible to treatment with iron orally and gives only partial responsiveness to parental iron therapy. Recently, about 42 distinct TMPRSS6 mutations those distributed entirely in all the distinct domains in extracellular regions have been reported in the humans. A novel case of a female from Japan with IRIDA is the one who carried a novel mutation (K253E) in the CUB (complement factor C1r/C1s, urchin embryonic growth factor, and BMP 1), which is a domain of the TMPRSS6 gene.
The importance of matriptase-2 in controlling iron balance was highlighted by human Genome-Wide Association Studies by identifying common TMPRSS6 mutations associated with abnormal hematological parametric values, including transferrin saturation, erythrocyte mean corpuscular volume, hemoglobin levels, and concentrations of iron in serum.,,
The TMPRSS6 expression is down-regulated by inflammation ex vivo experiments and experiments inside the living organisms. Bmp-Smad pathway signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems but it does not influence the down-regulation of TMPRSS6 by inflammation in the mice, but the downregulation occurs by a reduction in STAT5 phosphorylation. The positive regulation of TMPRSS6 expression is mediated by STAT5 by binding immediately to a STAT5 element present on the promoter region of TMPRSS6. The inhibition of TMPRSS6 through decreased STAT5 phosphorylation might be another mechanism through which inflammation stimulates the expression of hepcidin to regulate iron balance and immune response.
One frameshift mutation (p. Ala605ProfsX8) and four novel missense mutations (p. Glu114 Lys, p. Leu235Pro, p. Tyr418Cys, and p. Pro765Ala) have been observed in IRIDA patients. Both the catalytic and noncatalytic domains of matriptase-2 are subjected to changes due to this mutation.
Hepcidin usually involves in lowering of serum iron level. The increased production of hepcidin blocks the iron absorption, which results in anemia. Hepcidin regulates the expression of fetoprotein. If the iron storage is high, hepcidin level increases and it prevents the iron absorption in the intestine and the transport of recycled iron across the placenta. If the iron storage is low, the production of hepcidin is suppressed. The gene that encodes hepcidin is HAMP gene present on chromosome 19q13.1. This gene consists of 2637 bp along with 3 exons and 2 introns. Hepcidin is mainly expressed in the liver, whereas its expression can also be observed in the heart, brain, lung, prostate gland, tonsils, salivary gland, and trachea. The precursor for hepcidin is preprohepcidin. It contains 84 amino acids.,
|Regulation of Hepcidin|
BMP6 and iron not only stimulate the expression of hepcidin but also stimulates TMPRSS6, which acts as a negative controller for the expression of hepcidin. The TMPRSS6 expression modulation can act as a controller of negative feedback mechanism to prevent increasing the excessive hepcidin level by iron to help in maintaining the exact equilibrium of the levels of iron in our system. The increased hepcidin levels in patients with heritable IRIDA are the effect of surplus BMP6/hemojuvelin (Hjv) signaling pathway. The systemic regulation of iron in the human body is influenced by the regulated hepcidin expression.
Matriptase-2 inhibits the activation of hepcidin by splitting membrane Hjv has been demonstrated ex vivo. When it is overexpressed in HeLa cells, matriptase-2 enzyme gets interacted, and it stimulates the membrane Hjv splitting at the cell surface, which results in the generation of Hjv which is soluble in nature which is then discharged inside the cell medium. Moreover, as the response to chronic iron treatment and administration of BMP6 in mice, matriptase-2 levels are also elevated possibly to avoid increased production of hepcidin, suggesting a doubled action of matriptase-2 in the managing the exact systemic iron balance in a reflex action to iron.
The BMP and JAK2/STAT3 signaling pathways mediate the expression of hepcidin. Hepcidin expression in our human body is up-regulated under nonpathological conditions by the iron levels. Recent studies have confirmed the crucial roles of Hjv, hereditary hemochromatosis protein (also known as HFE protein), transferrin receptor 2, and matriptase-2 in the hepcidin regulation process in humans and animal models and also the essential roles of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models.,,
IDA is one of the most common predominant blood disorders worldwide. The IRIDA is the improper response of the body toward the iron supplementation, which is given as the treatment for IDA. It is due to certain alterations in matriptase-2 that manages hepcidin hormone, which is the master regulator of iron homeostasis.,, The pleotropic effect by the TMPRSS6 gene gives the variations in hepcidin concentrations, which in turn alters the iron metabolism., From the available literature, the TMPRSS6, hepcidin, and matriptase-2 have to be taken into consideration while analyzing anemic condition that does not respond to iron supplementation, which may be IRIDA condition. The interlinks between the IRIDA, hepcidin, and matriptase-2 have been well established in this review. The analysis of the signaling pathways of Hjv in IRIDA is yet to be understood.
IRIDA is a new disease entity that must be taken into consideration whenever undergoing a diagnosis of microcytic anemia. From the limited number of studies available, it is clear that TMPRSS6 polymorphisms are responsible for IRIDA. However, a lot remains to be discovered on the biology and functions of hepcidin. The signaling pathways are still has to be delineated.
The authors would like to acknowledge the Authorities of the Institution for providing the moral support in publishing this review.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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