Fetal protein

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Fetal proteins are high levels of proteins present during the fetal stage of development. Often related proteins assume similar roles after birth or in the embryo, in which case the fetal varieties are called fetal isoforms. Sometimes, the genes coding fetal isoforms occur adjacent to their adult homologues in the genome, and in those cases a locus control region often coordinates the transition from fetal to adult forms. In other cases fetal isoforms can be produced by alternate splicing using fetal exons to produce proteins that differ in only a portion of their amino acid sequence. In some situations the continuing expression of fetal forms can reveal the presence of a disease condition or serve as a treatment for diseases such as sickle cell anemia. Some well known examples include:

Transport of Fatty Acids During Gestation The Fatty acid transport system of human placenta.jpg
Transport of Fatty Acids During Gestation
Structure of Fetal Hemoglobin Structure of Fetal Hemoglobin (HbF).png
Structure of Fetal Hemoglobin

Fetal Hemoglobin is a member of erythrocytes called F-cells. [3] It is a tetramer protein with 2 alpha and 2 gamma subunits. This is different from adult hemoglobin because it has 2 alpha and 2 beta subunits.  Fetal hemoglobin is coded by a gene on chromosome 11. The gamma subunit on fetal hemoglobin contains a neutral and nonpolar amino acid at position 136, unlike the beta subunit of adult hemoglobin. The protein has a different structure than the adult protein because of this and helps in fetal development. Fetal hemoglobin has a main function to transfer oxygen from the pregnant person to the fetus during gestation. Fetal hemoglobin is vital in this system because it has a high affinity for oxygen. Fetal hemoglobin can be used to screen for pregnancy complications in the fetus and pregnant person. Fetal hemoglobin can also be used to treat sickle cell anemia. This hemoglobin is less likely to be affected by the disease because it has a higher affinity for oxygen. Hydroxyurea is used to increase the amount of fetal hemoglobin in an adult. [4] The fetal hemoglobin levels drop within 6 months of birth. Higher levels past 6 months can indicate blood diseases like thalassemia, leukemia, and sickle cell anemia. [5] Thalassemia is a blood condition where the blood cells do not carry enough oxygen. Leukemia is a cancer of the blood and sickle cell anemia is a condition where red blood cells don’t carry enough oxygen and collapse into a sickle cell shape. Fetal hemoglobin can also be found in the cord blood of the umbilical cord. The higher oxygen affinity allows more oxygen to transfer from the pregnant person to the fetus more efficiently. Common blood disorders with high levels of fetal hemoglobin show symptoms like anemia. [3]

Fetal Troponin T is a cardiac protein found in adults and infants. There are 4 Troponin T (TnT) isoforms found in fetal cardiac muscle. TnT1 and TnT2  which are also found in adult cardiac muscle. TnT1 are present along with two other isoforms. One of the other isoforms, a fetal cardiac TnT isoform, is also found in the fetal skeletal muscle. These isoforms are expressed differently in the fetus than in adult cardiac muscle. [6]

Fetal Troponin I (TnI) is a cardiac and skeletal protein found in adults and infants, with isomers specific to each. Two isoforms, TnIs and TnIc were found, with TnIs being more predominant during development. TnIc is the isoform found more in adults. TnIs levels decrease after birth and TnIc becomes the more predominant isoform in adults. [7]

α-FetoProtein (AFP) is part of the α1 globulin family of proteins. Alpha globulins are round transport proteins that have a wide variety of functions. Human AFP is produced in the liver, yolk sac, and GI tract of a fetus and dispersed into plasma. The mother of the fetus also obtains AFP directly from the fetus. [8] AFP was first found in human fetal serum in 1965 and determined to be the fetal version of albumin. In the 1980s a study found that fetal size and gestational age affects the concentration of AFP and that maternal, venous, and cord arterial AFP are associated with each other. Low AFP levels were found to show a lower risk pregnancy and high AFP determined that a pregnancy was higher risk along with other factors. The gene that codes for AFP on chromosome 4 is related to the genes that code for albumin, and all of them are clustered on the chromosome together. The AFP gene includes a promoter, 3 enhancers, and 2 silencers that assist in the regulation of AFP. Enhancers are blocked after birth to stop AFP production and to instead assist the albumin gene. [9] This protein resembles albumin and is the main protein found in fetal serum. [10] Human AFP is coded by a gene on chromosome 4, is made up of 591 amino acids and weighs between 68 and 72 kDa. This is a glycoprotein however human AFP only has carbohydrate side chains on one amino acid in the single chain. The protein contains cysteine which can create disulfide bonds, giving it a U or V shaped 2 dimensional structure by the single chain being folded into loops. The carbohydrate on Human AFP can bind lectin which is responsible for signaling in cells and immune responses. This can also mark where tumor sites have originated from and bound lectins can be targeted for drug therapy. Lectin affinity electrophoresis can be used to identify tumors due to binding of lectins. AFP can uptake fatty acids which contribute to energy generation and storage, plasma synthesis, and protein anchoring. It can also uptake lipoproteins which carry cholesterol throughout the body. AFP concentrations are abundant in the human fetus but decline after birth. [11] In adults a normal amount of AFP is 0-40nng/mL and high levels of this can indicate diseases, cancer, and fetal defects. In pregnant people AFP levels rise at 14 weeks until 32 weeks, and range between 10 and 150 ng/mL in the middle of gestation. This is why AFP can be used alongside other tests as a tumor marker protein in adults. [12] AFP is a single polypeptide chain with a half-life of 4–5 days. The protein that is normally expressed in a fetus can also be expressed in mesodermal and endodermal tumors. AFP can have a lower concentration with fetal defects and is used as a marker for that. A low AFP in a pregnant person can indicate Down syndrome. There are 3 forms of AFP: L1, L2, and L3. L1 is the form associated most commonly with liver disease and L3 is most commonly associated with malignant tumors. AFP-L3 can be used to detect hepatocellular carcinoma early on when compared to overall AFP levels. Liver cirrhosis can produce more AFP but a concentration over 200 can indicate hepatocellular carcinoma. [12] AFP can also be used to indicate effectiveness of chemotherapy. Some cancers like liver cancer will produce high amounts of AFP because the malignant cells can revert to how fetal cells work. When chemotherapy is effective, the AFP concentration will begin to decline back to normal range, whereas if it is ineffective the concentration won’t decline. Post surgery tests can indicate whether or not the malignant tumors were removed or if there are metastases that were missed. The test to measure concentration of AFP is a blood test. The most common types of cancers AFP indicates are in the liver, ovaries, and testicles. [13] A rare genetic condition called Ataxia Telangiectasia can also result in higher levels of AFP in people. [14]

Related Research Articles

<span class="mw-page-title-main">Hemoglobin</span> Oxygen-transport metalloprotein in red blood cells of most vertebrates

Hemoglobin, is the iron-containing oxygen-transport protein present in red blood cells (erythrocytes) of almost all vertebrates as well as the tissues of some invertebrate animals. Hemoglobin in blood carries oxygen from the respiratory organs to the other tissues of the body, where it releases the oxygen to enable aerobic respiration which powers the animal's metabolism. A healthy human has 12 to 20 grams of hemoglobin in every 100 mL of blood. Hemoglobin is a metalloprotein and chromoprotein.

<span class="mw-page-title-main">Hemoglobinopathy</span> Medical condition

Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.

<span class="mw-page-title-main">Anemia</span> Medical condition

Anemia or anaemia 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. The name is derived from Ancient Greek: ἀναιμία anaimia, meaning 'lack of blood', from ἀν- an-, 'not' and αἷμα haima, 'blood'. When anemia comes on slowly, the symptoms are often vague, such as tiredness, weakness, shortness of breath, headaches, and a reduced ability to exercise. When anemia is acute, symptoms may include confusion, feeling like one is going to pass out, loss of consciousness, and increased thirst. Anemia must be significant before a person becomes noticeably pale. Symptoms of anemia depend on how quickly hemoglobin decreases. Additional symptoms may occur depending on the underlying cause. Preoperative anemia can increase the risk of needing a blood transfusion following surgery. Anemia can be temporary or long term and can range from mild to severe.

<span class="mw-page-title-main">Alpha-fetoprotein</span> Fetal analogue of serum albumin

Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene. The AFP gene is located on the q arm of chromosome 4 (4q13.3). Maternal AFP serum level is used to screen for Down syndrome, neural tube defects, and other chromosomal abnormalities.

<span class="mw-page-title-main">Thalassemia</span> Medical condition

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time.

<span class="mw-page-title-main">Fetal hemoglobin</span> Oxygen carrier protein in the human fetus

Fetal hemoglobin, or foetal haemoglobin 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 to organs and tissues in the fetus. It is produced at around 6 weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition than adult forms of hemoglobin, allowing it to bind oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother's bloodstream, which occurs through the placenta found in the mother's uterus.

<span class="mw-page-title-main">Hydroxycarbamide</span> Medical drug

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 decreases the number of attacks. It is taken by mouth.

<span class="mw-page-title-main">Hemoglobin A</span> 4f CC w I/ pop m onf

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 erythrocytes, which transports oxygen from the lungs to the tissues. Hemoglobin A is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). Hemoglobin A2 (HbA2) is a less common adult form of hemoglobin and is composed of two alpha and two delta-globin subunits. This hemoglobin makes up 1-3% of hemoglobin in adults.

In oncology, AFP-L3 is an isoform of alpha-fetoprotein (AFP), a substance typically used in the triple test during pregnancy and for screening chronic liver disease patients for hepatocellular carcinoma (HCC). AFP can be fractionated by affinity electrophoresis into three glycoforms: L1, L2, and L3 based on the reactivity with the lectin Lens culinaris agglutinin (LCA). AFP-L3 binds strongly to LCA via an additional α 1-6 fucose residue attached at the reducing terminus of N-acetylglucosamine; this is in contrast to the L1 isoform. It is the L1 isoform which is typically associated with non-HCC inflammation of liver disease condition. The L3 isoform is specific to malignant tumors and its detected presence can serve to identify patients whom need increased monitoring for the development of HCC in high risk populations. AFP-L3% is now being considered as a tumor marker for the North American demographic.

<span class="mw-page-title-main">Sickle cell trait</span> Medical condition

Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene, but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele. Those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin.

<span class="mw-page-title-main">2,3-Bisphosphoglyceric acid</span> Chemical compound

2,3-Bisphosphoglyceric acid (2,3-BPG), also known as 2,3-diphosphoglyceric acid (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG).

<span class="mw-page-title-main">Beta thalassemia</span> Thalassemia characterized by the reduced or absent synthesis of the beta globin chains of hemoglobin

Beta 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 clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<span class="mw-page-title-main">Hemoglobin variants</span> Forms of hemoglobin caused by variations in genetics

Hemoglobin variants are different types of hemoglobin molecules, by different combinations of its subunits and/or mutations thereof. Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.

Hemoglobin Barts, abbreviated Hb Barts, is an abnormal type of hemoglobin that consists of four gamma globins. It is moderately insoluble, and therefore accumulates in the red blood cells. Hb Barts has an extremely high affinity for oxygen, so it cannot release oxygen to the tissue. Therefore, this makes it an inefficient oxygen carrier. As an embryo develops, it begins to produce alpha-globins at weeks 5–6 of development. When both of the HBA1 and HBA2 genes which code for alpha globins becomes dysfunctional, the affected fetuses will have difficulty in synthesizing a functional hemoglobin. As a result, gamma chains will accumulate and form four gamma globins. These gamma globins bind to form hemoglobin Barts. It is produced in the disease alpha-thalassemia and in the most severe of cases, it is the only form of hemoglobin in circulation. In this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth, unless intrauterine blood transfusion is performed.

<span class="mw-page-title-main">TNNT2</span> Protein-coding gene in the species Homo sapiens

Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.

<span class="mw-page-title-main">TNNI1</span> Protein-coding gene in the species Homo sapiens

Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction. Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

Elevated alpha-fetoprotein refers to a state where alpha-fetoprotein levels are outside of the reference range.

Hemoglobin H (Hb H)Disease, also called alpha-thalassemia intermedia, is a disease affecting hemoglobin, the oxygen carrying molecule within red blood cells. It is a form of Alpha-thalassemia which most commonly occurs due to deletion of 3 out of 4 of the α-globin genes.

<span class="mw-page-title-main">Hemoglobin Hopkins-2</span>

Hemoglobin Hopkins-2 is a mutation of the protein hemoglobin, 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. The mutation is the result of histidine 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.

References

  1. ↑ Kal-Koshvandi AT (July 2020). "Recent advances in optical biosensors for the detection of cancer biomarker α-fetoprotein (AFP)". TrAC Trends in Analytical Chemistry. 12: 115920. doi:10.1016/j.trac.2020.115920. S2CID   219517182.
  2. ↑ J Verheul TC, Trinh VT, Vázquez O, Philipsen S (December 2020). "Targeted Protein Degradation as a Promising Tool for Epigenetic Upregulation of Fetal Hemoglobin". ChemMedChem. 15 (24): 2436–2443. doi:10.1002/cmdc.202000574. PMC   7756256 . PMID   33002296.
  3. 1 2 says, Via Peter (2018-03-29). "Fetal Hemoglobin". News-Medical.net. Retrieved 2023-04-27.
  4. ↑ Kaufman, Daniel P.; Khattar, Jasmin; Lappin, Sarah L. (2023), "Physiology, Fetal Hemoglobin", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   29763187 , retrieved 2023-04-27
  5. ↑ "Hemoglobin (Fetal) - Health Encyclopedia - University of Rochester Medical Center". www.urmc.rochester.edu. Retrieved 2023-04-27.
  6. ↑ Anderson, P A; Malouf, N N; Oakeley, A E; Pagani, E D; Allen, P D (November 1991). "Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle". Circulation Research. 69 (5): 1226–1233. doi: 10.1161/01.RES.69.5.1226 . ISSN   0009-7330.
  7. ↑ Sasse, S; Brand, N J; Kyprianou, P; Dhoot, G K; Wade, R; Arai, M; Periasamy, M; Yacoub, M H; Barton, P J (May 1993). "Troponin I gene expression during human cardiac development and in end-stage heart failure". Circulation Research. 72 (5): 932–938. doi: 10.1161/01.RES.72.5.932 . ISSN   0009-7330.
  8. ↑ "Cancer Markers - Alpha-Fetoprotein (AFP) - scrippslabs.com". scrippslabs.com. Retrieved 2023-04-27.
  9. ↑ Yeh, Shiou-Hwei; Lin, Ming-Wei; Lu, Shu-Fen; Wu, Dai-Chen; Tsai, Shih-Feng; Tsai, Ching-Yi; Lai, Ming-Yang; Hsu, Hey-Chi; Chen, Ding-Shinn; Chen, Pei-Jer (October 2004). "Allelic loss of chromosome 4q21 ≍ 23 associates with hepatitis B Virus—related hepatocarcinogenesis and elevated alpha-fetoprotein". Hepatology. 40 (4): 847–854. doi:10.1002/hep.1840400414.
  10. ↑ Crandall, B. F. (1981). "Alpha-fetoprotein: a review". Critical Reviews in Clinical Laboratory Sciences. 15 (2): 127–185. doi:10.3109/10408368109105870. ISSN   1040-8363. PMID   6169490.
  11. ↑ Kal-Koshvandi, Afsaneh Taheri (2020-07-01). "Recent advances in optical biosensors for the detection of cancer biomarker α-fetoprotein (AFP)". TrAC Trends in Analytical Chemistry. 128: 115920. doi:10.1016/j.trac.2020.115920. ISSN   0165-9936.
  12. 1 2 Adigun, Oluwaseun O.; Yarrarapu, Siva Naga S.; Zubair, Muhammad; Khetarpal, Shailesh (2023), "Alpha Fetoprotein", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   28613501 , retrieved 2023-04-27
  13. ↑ "Alpha Fetoprotein (AFP) Tumor Marker Test: MedlinePlus Medical Test". medlineplus.gov. Retrieved 2023-04-27.
  14. ↑ "Alpha-Fetoprotein Tumor Marker (Blood) - Health Encyclopedia - University of Rochester Medical Center". www.urmc.rochester.edu. Retrieved 2023-04-27.
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