DOCSLIB.ORG

Genetic Disorders Associated with Metal Metabolism

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Disorders Associated with Metal Metabolism cells Review Genetic Disorders Associated with Metal Metabolism Muhammad Umair 1 and Majid Alfadhel 1,2,* 1 Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGH), P.O Box 3660, Riyadh 11481, Saudi Arabia; [email protected] 2 Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical P.O Box 22490, Riyadh 11426, Saudi Arabia * Correspondence: [email protected]; Tel.: +(966)-11-805-3560; Fax: +(966)-11-805-5555 Received: 17 October 2019; Accepted: 5 December 2019; Published: 9 December 2019 Abstract: Genetic disorders associated with metal metabolism form a large group of disorders and mostly result from defects in the proteins/enzymes involved in nutrient metabolism and energy production. These defects can affect different metabolic pathways and cause mild to severe disorders related to metal metabolism. Some disorders have moderate to severe clinical consequences. In severe cases, these elements accumulate in different tissues and organs, particularly the brain. As they are toxic and interfere with normal biological functions, the severity of the disorder increases. However, the human body requires a very small amount of these elements, and a deficiency of or increase in these elements can cause different genetic disorders to occur. Some of the metals discussed in the present review are copper, iron, manganese, zinc, and selenium. These elements may play a key role in the pathology and physiology of the nervous system. Keywords: metal metabolism; genetic disorders; copper; iron; manganese; zinc; selenium 1. Introduction Metal ions play an important role in several biological processes that have both structural and functional importance. Human beings gain an adequate amount of nutrient metals from their daily diet, but need to avoid a toxic or an excess amount of metals for an ideal health. Both an imbalance in the amount of nutrient metals in the body and exposure to toxic metals are associated with severe health problems. They are linked to several abnormalities, including cardiovascular diseases, neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease), and metabolic disorders [1–5]. The toxicity of and pathways involved in metal imbalances are now considered to be highly active areas of biomedical research. The findings of these studies might inspire us to develop new classes of therapeutic strategies and help us to understand metal metabolism [5,6]. 1.1. Transfer of Groups “Transitional elements” or “transitional metals” are those elements that are present in the d-series (Groups 3 to 12) of the periodic table. All of the transitional or trace metals also participate in reactions that involve the transfer of specific groups. These include either phosphorylation (when a phosphate residue is transferred) or dephosphorylation (when a phosphate residue is removed). Similarly, glycosylation is the process by which a sugar residue is transferred [7]. 1.2. Neurotoxicity Neurotoxicity results in the accumulation of elements in the brain, such as copper, selenium, iron, and manganese, and can lead to different types of brain-associated disorders. Specific parts Cells 2019, 8, 1598; doi:10.3390/cells8121598 www.mdpi.com/journal/cells Cells 2019, 8, x FOR PEER REVIEW 2 of 22 Neurotoxicity results in the accumulation of elements in the brain, such as copper, selenium, Cells 2019, 8, 1598 2 of 23 iron, and manganese, and can lead to different types of brain-associated disorders. Specific parts of the brain, such as the substantia nigra and the basal ganglia, are predominantly exposed to such changes.of the brain, Some such of the as themetals substantia discussed nigra in andthe present the basal review ganglia, are arecopper, predominantly iron, manganese, exposed zinc, to suchand selenium,changes. Somewhich of play the metalsa very discussedimportant in role the in present human review biology. are copper,Several iron,disorders manganese, that involve zinc, and an accumulationselenium, which of different play a very metal important elements role in the in humanhuman biology.brain have Several been disordersreported in that the involve literature an andaccumulation are discussed of di inff erentthe present metal review elements [4,8 in–12 the]. Some human disorders brain have that beenare due reported to an accumulation in the literature of manganese,and are discussed copper, in or the iron present and caus reviewe neurotoxicity [4,8–12]. Some are summarized disorders that in Table are due 1. toThe an present accumulation review willof manganese, highlight: i) copper, Disorders or iron associated and cause with neurotoxicity zinc homeostasis are summarized; ii) disorders in Tableassociated1. The with present iron homeostasisreview will; highlight: iii) disorders (i) Disorders associated associated with copper with zinc homeostasis homeostasis;; iv) (ii) disorders disorders associated associated with with manironganese homeostasis; homeostasis (iii) disorders; and v) d associatedisorders associated with copper with homeostasis; selenium homeostasis (iv) disorders. associated with manganese homeostasis; and (v) disorders associated with selenium homeostasis. 2. Zinc Homeostasis 2. Zinc Homeostasis Zinc plays a very important role in the human body and acts as a cofactor for several enzymes and transcriptionZinc plays a veryfactors important that contain role in modules the human for bodybinding and DNA acts as and a cofactor RNA (zinc for several fingers) enzymes, including and alkalinetranscription phosphatase, factors that lactate contain dehydrogenase, modules for binding ornithine DNA transcarbamylase, and RNA (zinc fingers), superoxide including dismutase, alkaline carbonicphosphatase, anhydrase, lactate dehydrogenase,DNA and RNA ornithinepolymerases, transcarbamylase, matrix metalloproteinases, superoxide dismutase, insulin-degrading carbonic enzymeanhydrase,s, N- DNAacyl D and-aspartate RNA polymerases, acylase, and matrixalcohol metalloproteinases, dehydrogenase [13] insulin-degrading. Zinc metalloenzymes enzymes, are involvedN-acyl D-aspartate in the regulation acylase,and of alcoholdifferent dehydrogenase metabolic pathways [13]. Zinc and metalloenzymes have structural, are involvedcatalytic, in and the regulatoryregulation offunctions different [ metabolic14]. Although pathways zinc andis important have structural, to proper catalytic, regulation and regulatory of several functions important [14]. physiologicalAlthough zinc functions, is important both to properan excess regulation and a deficiency of several of important zinc have physiological been associated functions, with bothseveral an conditionsexcess and (Figure a deficiency 1). of zinc have been associated with several conditions (Figure1). SeveralSeveral members members of of the the SLC39ASLC39A familyfamily encode encode for for different different zinc/iron zinc/iron-regulated-regulated transporter transporter-like-like protein ( (ZIP)ZIP) transporters (ZIP1 (ZIP1–6,–6, 8 8–10,–10, 12 12,, and 14). Their Their main main function function is is t thehe uptake uptake of of zinc zinc at at the the cellcell surface surface;; however, however, some family members also also have the ability to transport manganese, iron iron,, and and cadmiumcadmium [[1515].]. Similarly,Similarly, it hasit has been been reported reported that boththat SLC39A14both SLC39A14and SLC39A8 and SLC39A8have similar have functions similar functionsand mediate and manganese mediate uptakemanganese at the uptake cell surface at the [16 ].cell Deficiencies surface in[16 these]. Deficiencies ZIP transporters in these result ZIP in transportersdifferent disorders result in in different humans (Figuredisorders2). in Many humans disorders (Figure have 2). Many been associateddisorders have with been zinc deficiency;associated withhowever, zinc deficiency only a few; arehowever discussed, only here. a few are discussed here. Figure 1. A schematic representation of zinc deficiency as compared to zinc intoxication. Figure 1. A schematic representation of zinc deficiency as compared to zinc intoxication. Cells 2019, 8, 1598 3 of 23 Cells 2019, 8, x FOR PEER REVIEW 3 of 22 FigureFigure 2. 2. SLC39ASLC39A familyfamily members members (zinc/iron (zinc/iron-regulated-regulated transporter transporter-like-like protein protein (ZIP (ZIP)) transporters) transporters) SLC30A andand their their role atat thethe cellular cellular level. level. Zn Zn transporters transporters belong belong to the to the SLC30Afamily. family. These causeThese di causfferente disordersdisorders in in humans. humans. Cells 2019, 8, 1598 4 of 23 Cells 2019, 8, 1598 5 of 23 Table 1. Disorders that are due to an accumulation of manganese, copper, or iron and cause neurotoxicity. Disorders Transition Metal Inheritance Gene OMIM Gene Function Symptoms Autosomal Dystonia, cock-walk gait Hypermanganesemia with dystonia 1 Manganese SLC30A10 613280 Manganese transporter recessive Parkinsonism Autosomal Progressive dystonia and bulbar Hypermanganesemia with dystonia 2 Manganese SLC39A14 617013 Manganese transporter recessive dysfunction Autosomal Dysarthria, dysphagia, Wilson’s disease Copper ATP7B 277900 Copper transporter recessive tremor, dystonic rigidity Acaeruloplasminaemia, Cerebellar ataxia, Autosomal Chorea, ataxia, dystonia, Iron CP 604290 Ferroxidase Hypoceruloplasminemia recessive Parkinsonism,
Load more

Recommended publications
  • Iron Regulation by Hepcidin
    Iron regulation by hepcidin Ningning Zhao, … , An-Sheng Zhang, Caroline A. Enns J Clin Invest. 2013;123(6):2337-2343. https://doi.org/10.1172/JCI67225. Science in Medicine Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β- thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload. Find the latest version: https://jci.me/67225/pdf Science in medicine Iron regulation by hepcidin Ningning Zhao, An-Sheng Zhang, and Caroline A. Enns Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA. Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physi- ologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia.
    [Show full text]
  • Iron Transport Proteins: Gateways of Cellular and Systemic Iron Homeostasis
    Iron transport proteins: Gateways of cellular and systemic iron homeostasis Mitchell D. Knutson, PhD University of Florida Essential Vocabulary Fe Heme Membrane Transport DMT1 FLVCR Ferroportin HRG1 Mitoferrin Nramp1 ZIP14 Serum Transport Transferrin Transferrin receptor 1 Cytosolic Transport PCBP1, PCBP2 Timeline of identification in mammalian iron transport Year Protein Original Publications 1947 Transferrin Laurell and Ingelman, Acta Chem Scand 1959 Transferrin receptor 1 Jandl et al., J Clin Invest 1997 DMT1 Gunshin et al., Nature; Fleming et al. Nature Genet. 1999 Nramp1 Barton et al., J Leukocyt Biol 2000 Ferroportin Donovan et al., Nature; McKie et al., Cell; Abboud et al. J. Biol Chem 2004 FLVCR Quigley et al., Cell 2006 Mitoferrin Shaw et al., Nature 2006 ZIP14 Liuzzi et al., Proc Natl Acad Sci USA 2008 PCBP1, PCBP2 Shi et al., Science 2013 HRG1 White et al., Cell Metab DMT1 (SLC11A2) • Divalent metal-ion transporter-1 • Former names: Nramp2, DCT1 Fleming et al. Nat Genet, 1997; Gunshin et al., Nature 1997 • Mediates uptake of Fe2+, Mn2+, Cd2+ • H+ coupled transporter (cotransporter, symporter) • Main roles: • intestinal iron absorption Illing et al. JBC, 2012 • iron assimilation by erythroid cells DMT1 (SLC11A2) Yanatori et al. BMC Cell Biology 2010 • 4 different isoforms: 557 – 590 a.a. (hDMT1) Hubert & Hentze, PNAS, 2002 • Function similarly in iron transport • Differ in tissue/subcellular distribution and regulation • Regulated by iron: transcriptionally (via HIF2α) post-transcriptionally (via IRE) IRE = Iron-Responsive Element Enterocyte Lumen DMT1 Fe2+ Fe2+ Portal blood Enterocyte Lumen DMT1 Fe2+ Fe2+ Fe2+ Fe2+ Ferroportin Portal blood Ferroportin (SLC40A1) • Only known mammalian iron exporter Donovan et al., Nature 2000; McKie et al., Cell 2000; Abboud et al.
    [Show full text]
  • Hepcidin Is Not a Marker of Chronic Inflammation in Atherosclerosis Hepcidin Aterosklerozda Kronik Inflamasyonun Bir Göstergesi De¤Ildir
    Original Investigation Orijinal Araflt›rma 239 Hepcidin is not a marker of chronic inflammation in atherosclerosis Hepcidin aterosklerozda kronik inflamasyonun bir göstergesi de¤ildir Aytekin O¤uz, Mehmet Uzunlulu, Nezih Hekim* Department of Internal Medicine, Göztepe Training and Research Hospital, ‹stanbul, Turkey *Pakize Tarz› Laboratory, ‹stanbul, Turkey ABSTRACT Objective: To investigate the relationship between atherosclerosis, an inflammatory disease and hepcidin which is reported as an indi- cator of inflammation Methods: A total of 75 subjects between 40 and 70 years of age were included in the study. The patient group consisted of 40 stable pa- tients who had previously experienced an atherosclerotic event (18 women, 22 men; mean age 56.4±7.1 years). There were two control groups. The first control group consisted of 19 healthy subjects (11 women, 8 men; mean age 52.6± 7.4 years), while the second group inc- luded 16 patients (11 women, 5 men; mean age 56.5±9.3 years) with rheumatoid arthritis and anemia (diseased control group). Hepcidin measurement was performed using Hepcidin Prohormone ELISA (Solid Phase Enzyme-Linked Immunosorbent Assay) test kit. Results: Mean serum hepcidin levels were 243.2±48.8 ng/ml, 374.5±86.4 ng/ml, and 234±59.9 ng/ml in the patient group, in diseased cont- rols, and in healthy controls, respectively. Hepcidin levels were higher in diseased controls compared to the patient group and healthy controls (p=0.001). There were no significant differences between the patient group and healthy controls. Conclusion: These findings did not support the hypothesis that hepcidin levels could be increased in atherosclerotic cardiovascular di- seases as a marker of chronic inflammation.
    [Show full text]
  • Ferroportin Mutation in Autosomal Dominant Hemochromatosis: Loss of Function, Gain in Understanding
    Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding Robert E. Fleming, William S. Sly J Clin Invest. 2001;108(4):521-522. https://doi.org/10.1172/JCI13739. Commentary Normal iron homeostasis requires close matching of dietary iron absorption with body iron needs (1). Hereditary hemochromatosis (HH), a common abnormality of iron metabolism, is characterized by excess absorption of dietary iron despite elevated stores, and secondary damage to the liver, pancreas, and other organs (2). Classic HH is caused by mutation of the HFE gene and is inherited as an autosomal recessive trait. However, a substantial percentage of individuals with hemochromatosis, especially in non–Northern European populations, have no mutations in HFE (3). Many such cases differ from classic HH in the relative distribution of iron between the plasma, hepatocytes, and reticuloendothelial (RE) cells (4). Pietrangelo et al. recently reported a pedigree with atypical hemochromatosis inherited as an autosomal dominant trait (5). In this issue of the JCI, Montosi et al. report the surprising finding that the gene mutated in these patients (SLC11A3) encodes the iron export protein ferroportin1 (also known as IREG1, or MTP1) (6). They conclude that the identified mutation (A77D) probably results in loss of ferroportin1 function, suggesting that the affected individuals are haploinsufficient for this gene product. In a nearly simultaneous report, Njajou et al. (7) describe a similar pedigree with autosomal dominant hemochromatosis and a different missense mutation (N144H) in the same gene. Njajou et al., however, conclude that the iron overload phenotype was likely […] Find the latest version: https://jci.me/13739/pdf Ferroportin mutation in autosomal Commentary dominant hemochromatosis: loss See related article, pages 619–623.
    [Show full text]
  • Genes in Eyecare Geneseyedoc 3 W.M
    Genes in Eyecare geneseyedoc 3 W.M. Lyle and T.D. Williams 15 Mar 04 This information has been gathered from several sources; however, the principal source is V. A. McKusick’s Mendelian Inheritance in Man on CD-ROM. Baltimore, Johns Hopkins University Press, 1998. Other sources include McKusick’s, Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders. Baltimore. Johns Hopkins University Press 1998 (12th edition). http://www.ncbi.nlm.nih.gov/Omim See also S.P.Daiger, L.S. Sullivan, and B.J.F. Rossiter Ret Net http://www.sph.uth.tmc.edu/Retnet disease.htm/. Also E.I. Traboulsi’s, Genetic Diseases of the Eye, New York, Oxford University Press, 1998. And Genetics in Primary Eyecare and Clinical Medicine by M.R. Seashore and R.S.Wappner, Appleton and Lange 1996. M. Ridley’s book Genome published in 2000 by Perennial provides additional information. Ridley estimates that we have 60,000 to 80,000 genes. See also R.M. Henig’s book The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, published by Houghton Mifflin in 2001 which tells about the Father of Genetics. The 3rd edition of F. H. Roy’s book Ocular Syndromes and Systemic Diseases published by Lippincott Williams & Wilkins in 2002 facilitates differential diagnosis. Additional information is provided in D. Pavan-Langston’s Manual of Ocular Diagnosis and Therapy (5th edition) published by Lippincott Williams & Wilkins in 2002. M.A. Foote wrote Basic Human Genetics for Medical Writers in the AMWA Journal 2002;17:7-17. A compilation such as this might suggest that one gene = one disease.
    [Show full text]
  • Hepcidin Therapeutics
    pharmaceuticals Review Hepcidin Therapeutics Angeliki Katsarou and Kostas Pantopoulos * Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(514)-340-8260 (ext. 25293) Received: 3 November 2018; Accepted: 19 November 2018; Published: 21 November 2018 Abstract: Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art. Keywords: iron metabolism; hepcidin; ferroportin; hemochromatosis; anemia 1. Systemic Iron Homeostasis Iron is an essential constituent of cells and organisms and participates in vital biochemical activities, such as DNA synthesis, oxygen transfer, and energy metabolism. The biological functions of iron are based on its capacity to interact with proteins and on its propensity to switch between the ferrous (Fe2+) and ferric (Fe3+) oxidation states.
    [Show full text]
  • Hepcidin the Key Regulator of Iron in the Blood St
    Hepcidin The Key Regulator of Iron in the Blood St. Dominic Middle School SMART Team Eclaire Jessup, Dominic Kowalik, Allyssa Larcheid, Samuel Larcheid, Claire Lois, Sara Maslowski, I. Introduction to Hepcidin and Iron Homeostasis Emma Pittman, Joseph Platz, Marissa Puccetti, Tyler Shecterle, Nicole Simson, Emma Wenger Abstract Hepcidin, a peptide hormone, is the key regulator of plasma iron levels in humans, and is known to play an important role in Iron is found everywhere on Earth and is essential to life. The human body contains 3-4 grams of iron Teacher: Ms. LaFlamme Mentor: Dr. Matthew S. Karafin, various human diseases, such as hemochromatosis. Hepcidin inhibits the entry of iron into circulation by binding to and over fifty percent is found in red blood cells (RBCs). Without iron, the oxygen carrying protein ferroportin, a trans-membrane iron export channel found primarily on enterocytes, hepatocytes and macrophages where iron Medical College of Wisconsin, The Blood Center of Wisconsin hemoglobin that fills RBCs cannot be made and the bone marrow cannot carry out erythropoiesis is sequestered. When hepcidin binds to ferroportin, both are drawn into the cell by endocytosis and degraded in a lysosome. When hepcidin levels increase, ferroportin levels on cells decrease and iron cannot be released from cells into the blood. (RBC production). All iron in the body is absorbed from the diet in the duodenum. Hepcidin production by the liver is affected by erythropoiesis in bone marrow, blood oxygenation, certain inflammatory The peptide hormone, hepcidin, controls the release of the dietary iron from duodenal enterocytes III. Hepcidin Structure & Function cytokines, intracellular iron storage, and plasma transferrin.
    [Show full text]
  • Syllabus METAL ION EXCESS TOXICITY
    Syllabus Metalionexcesstoxicity-Feexcesstoxicity-Africansiderosis,hemosiderosis, hemochromatosis(bronzediabetes)anddetoxification.Cuexcesstoxicity:Wilson’sdisease andtreatment. Heavymetaliontoxicity:Hg,Pb,Cd,Astoxiceffects–mechanismoftoxiceffects.Heavy metaltoxicitytreatment-chelationtherapy:chelatingagentsforHg,Pb,Cd,Astoxicity. Metalcomplexesasdrugs:cis-plainasanticanceragent:mechanismofactionandside effects;goldcomplexesasantiarthriticdrugs-chrysotherapy.Metalcomplexesindiagnosis- Gdcomplexesinmagneticresonanceimaging(MRI). METALIONEXCESSTOXICITY Ironexcesstoxicity ü ItisduetoaccidentalintakeofFeSO4tabletscausingerosionofthegastrointestinal tract. ü Hemochomatosisisageneticdisorder,depositionofironoccursinvitalorganslike liver,spleen,pancreas,skinetc.Itleadstobronzepigmentationontheskiniscalled bronzediabetes. ü Siderosis(depositionofFeOdustinthelungs)isassociatedwithexcessofiron. ü AfricansiderosisisanironoverloaddisorderfirstobservedamongpeopleofSouthern AfricaandCentralAfrica.Dietaryironoverloadistheconsumptionoflargeamount ofhome-brewedbeerwithhighamountofironcontentinit. Detoxification : Siderophore desferrioxamine is a chelating antidote used for Fe removal Coppertoxicity Copper is a principal component of several metalloproteins and some naturally occurring pigments.Ahealthyadultpossessescopperbetween200to300mgandthehighestamountis concentratedin the locus of brain. Wilson’sdiseaseand Menkes’ kinky hair syndromeare associatedwithageneticdisorderinthemetabolismofcopper. Wilson’sdisease ü In Wilson'sdisease,the copper-content
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Chelation Therapy
    Corporate Medical Policy Chelation Therapy File Name: chelation_therapy Origination: 12/1995 Last CAP Review: 2/2021 Next CAP Review: 2/2022 Last Review: 2/2021 Description of Procedure or Service Chelation therapy is an established treatment for the removal of metal toxins by converting them to a chemically inert form that can be excreted in the urine. Chelation therapy comprises intravenous or oral administration of chelating agents that remove metal ions such as lead, aluminum, mercury, arsenic, zinc, iron, copper, and calcium from the body. Specific chelating agents are used for particular heavy metal toxicities. For example, desferroxamine (not Food and Drug Administration [FDA] approved) is used for patients with iron toxicity, and calcium-ethylenediaminetetraacetic acid (EDTA) is used for patients with lead poisoning. Note that disodium-EDTA is not recommended for acute lead poisoning due to the increased risk of death from hypocalcemia. Another class of chelating agents, called metal protein attenuating compounds (MPACs), is under investigation for the treatment of Alzheimer’s disease, which is associated with the disequilibrium of cerebral metals. Unlike traditional systemic chelators that bind and remove metals from tissues systemically, MPACs have subtle effects on metal homeostasis and abnormal metal interactions. In animal models of Alzheimer’s disease, they promote the solubilization and clearance of β-amyloid protein by binding to its metal-ion complex and also inhibit redox reactions that generate neurotoxic free radicals. MPACs therefore interrupt two putative pathogenic processes of Alzheimer’s disease. However, no MPACs have received FDA approval for treating Alzheimer’s disease. Chelation therapy has also been investigated as a treatment for other indications including atherosclerosis and autism spectrum disorder.
    [Show full text]
  • Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened.
    [Show full text]
  • Nr 1. Each Patient Suffering from Acute Coronary Syndrome Must Be Treated With
    SED - 3 - VERSION I February 2009 Nr 1. Each patient suffering from acute coronary syndrome must be treated with: A. Acetylsalicylic acid (ASA). B. ASA or clopidogrel. C. ASA and clopidogrel. D. depending on the type of myocardial infarction – ASA and clopidogrel or ASA only. E. depending on the mode of treatment (invasive vs noninvasive) – ASA and clopidogrel or ASA only. Nr 2. A patient in the class IV of Killip-Kimball classification has: A. pulmonary oedema. B. cardiogenic shock. C. blood retention (haemostasis) below the level of inferior angles of scapulae. D. no signs of heart insufficiency. E. chronic heart insufficiency, previously at least in NYHA class III. Nr 3. Schőnlein-Henoch purpura is a vasculitis that: A. is characterized by nephritic syndrome with cANCA antibodies. B. may present as rapidly progressive glomerulonephritis. C. is often accompanied by granulomas in the lungs. D. is typically treated by a surgical excision of granuloma. E. is typically treated by nephrectomy of the kidney with granulomas. Nr 4. Which of the below given drugs can cause hyperkalemia? 1) angiotensin converting enzyme inhibitors. 2) loop diuretics. 3) aldosterone antagonist. 4) thiazide. 5) indapamide. The correct answer is: A. 1,3. B. 1,2,3. C. 1,3,4. D. 1,3,5. E. all of the above. Nr 5. Which of the below is an absolute contraindication to thrombolytic therapy in acute myocardial infarction: A. age above 75. B. suspected dissecting aortic aneurysm. C. past cerebral stroke 2 years ago. D. high blood pressure >175/110 mmHg. E. invasive cardiology unit available on duty, which can be reached within 90 minutes.
    [Show full text]