scholarly journals The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism patients

2019 ◽  
Author(s):  
Giuliana Giannuzzi ◽  
Paul J. Schmidt ◽  
Eleonora Porcu ◽  
Gilles Willemin ◽  
Katherine M. Munson ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Copy Number ◽  
Iron Homeostasis ◽  
Copy Number Variations ◽  
Rapid Expansion ◽  
Deficiency Anemia ◽  
Zinc Protoporphyrin ◽  
The Uk ◽  
Human Specific

AbstractHuman-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy number variations, one of the most common genetic causes of autism. These copy number polymorphic duplications are under positive selection and include 3–8 copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, P=4e-7, OR=5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, with 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, we found an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, P=1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The deletion and Bola2-deficient mice showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc protoporphyrin to heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo and its expansion has a potential adaptive role in protecting against iron deficiency.

scholarly journals Zinc Protoporphyrin Is a Reliable Marker of Functional Iron Deficiency in Patients with Inflammatory Bowel Disease

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 366
Author(s):  
Eleni Leventi ◽  
Aysegül Aksan ◽  
Carl Thomas Nebe ◽  
Jürgen Stein ◽  
Karima Farrag
Keyword(s):  
Inflammatory Bowel Disease ◽  
Iron Deficiency ◽  
Chronic Inflammation ◽  
Bowel Disease ◽  
Iron Homeostasis ◽  
Transferrin Saturation ◽  
Deficiency Anemia ◽  
Zinc Protoporphyrin ◽  
Anemia Of Chronic Disease ◽  
Inflammatory Bowel

Iron deficiency (ID) is a common manifestation of inflammatory bowel disease (IBD), arising primarily due to chronic inflammation and/or blood loss. There is no gold standard for ID diagnosis, which is often complicated by concomitant inflammation. Zinc protoporphyrin (ZnPP) correlates with parameters of iron homeostasis and has been identified as a promising marker for ID, irrespective of inflammation. We investigated the diagnostic performance of ZnPP in ID, iron deficiency anemia, anemia of chronic disease and mixed anemia in a cross-sectional study in 130 patients with IBD. Different parameters were compared by receiver operator characteristic (ROC) analysis as detectors of iron-restricted erythropoiesis (IRE). IRE was detected in 91 patients (70.0%); fifty-nine (64.8%) had absolute ID and 23 (25.4%) functional ID. When inflammation was present, ZnPP was a more reliable sole biomarker of IRE than MCV, transferrin saturation (TSAT) or ferritin (AUC; 0.855 vs. 0.763, 0.834% and 0.772, respectively). The specificity of TSAT was significantly lower than ZnPP when inflammation was present (38% vs. 71%, respectively). We conclude that ZnPP is a reliable biomarker of functional ID in patients with IBD and more dependable than ferritin or TSAT, which are influenced by chronic inflammation. We propose that ZnPP may also have utility in patients with other chronic diseases.

scholarly journals Hepcidin regulates ferroportin expression and intracellular iron homeostasis of erythroblasts

Blood ◽  
2011 ◽  
Vol 118 (10) ◽  
pp. 2868-2877 ◽  
Author(s):  
De-Liang Zhang ◽  
Thomas Senecal ◽  
Manik C. Ghosh ◽  
Hayden Ollivierre-Wilson ◽  
Tiffany Tu ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Fine Tuning ◽  
Deficiency Anemia ◽  
Iron Release ◽  
Intracellular Iron ◽  
Subsequent Increase ◽  
A Cell ◽  
Export Protein

Abstract The iron-regulatory hormone, hepcidin, regulates systemic iron homeostasis by interacting with the iron export protein ferroportin (FPN1) to adjust iron absorption in enterocytes, iron recycling through reticuloendothelial macrophages, and iron release from storage in hepatocytes. We previously demonstrated that FPN1 was highly expressed in erythroblasts, a cell type that consumes most of the serum iron for use in hemoglobin synthesis. Herein, we have demonstrated that FPN1 localizes to the plasma membrane of erythroblasts, and hepcidin treatment leads to decreased expression of FPN1 and a subsequent increase in intracellular iron concentrations in both erythroblast cell lines and primary erythroblasts. Moreover, injection of exogenous hepcidin decreased FPN1 expression in BM erythroblasts in vivo, whereas iron depletion and associated hepcidin reduction led to increased FPN1 expression in erythroblasts. Taken together, hepcidin decreased FPN1 expression and increased intracellular iron availability of erythroblasts. We hypothesize that FPN1 expression in erythroblasts allows fine-tuning of systemic iron utilization to ensure that erythropoiesis is partially suppressed when nonerythropoietic tissues risk developing iron deficiency. Our results may explain why iron deficiency anemia is the most pronounced early manifestation of mammalian iron deficiency.

scholarly journals Effects of naturally occurring flavonoids on ferroportin expression in the spleen in iron deficiency anemia in vivo

RSC Advances ◽  
2017 ◽  
Vol 7 (38) ◽  
pp. 23238-23245 ◽  
Author(s):  
Maryam Mazhar ◽  
Shaheen Faizi ◽  
Anum Gul ◽  
Nurul Kabir ◽  
Shabana U. Simjee
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Deficiency Anemia ◽  
Iron Supplement ◽  
Naturally Occurring ◽  
Key Players

Polyphenols with iron supplement exert variable effects on key players of iron homeostasis in iron deficiency anemia.

Maturation, iron deficiency, and ligands in enteric radioiron transport in vitro

1963 ◽  
Vol 204 (1) ◽  
pp. 171-175 ◽  
Author(s):  
W. S. Ruliffson ◽  
J. M. Hopping
Keyword(s):  
Ascorbic Acid ◽  
Iron Deficiency ◽  
Iron Absorption ◽  
Deficiency Anemia ◽  
Anaerobic Incubation ◽  
Reverse Effect ◽  
Factors Affecting ◽  
Everted Gut Sac

The effects in rats, of age, iron-deficiency anemia, and ascorbic acid, citrate, fluoride, and ethylenediaminetetraacetate (EDTA) on enteric radioiron transport were studied in vitro by an everted gut-sac technique. Sacs from young animals transported more than those from older ones. Proximal jejunal sacs from anemic animals transported more than similar sacs from nonanemic rats, but the reverse effect appeared in sacs formed from proximal duodenum. When added to media containing ascorbic acid or citrate, fluoride depressed transport as did anaerobic incubation in the presence of ascorbic acid. Anaerobic incubation in the presence of EDTA appeared to permit elevated transport. Ascorbic acid, citrate, and EDTA all enhanced the level of Fe59 appearing in serosal media. These results appear to agree with previously established in vivo phenomena and tend to validate the in vitro method as one of promise for further studies of factors affecting iron absorption and of the mechanism of iron absorption.

Detection of iron-deficiency anemia in hospitalized patients by zinc protoporphyrin

1996 ◽  
Vol 244 (1) ◽  
pp. 91-101 ◽  
Author(s):  
Shan S. WongA ◽  
Ala S. Qutishat ◽  
Jason Lange ◽  
Terrie G. Gornet ◽  
L. Maximilian Buja
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Hospitalized Patients ◽  
Deficiency Anemia ◽  
Zinc Protoporphyrin

Iron Homeostasis and Disorders in Dogs and Cats: A Review

2011 ◽  
Vol 47 (3) ◽  
pp. 151-160 ◽  
Author(s):  
Jennifer L. McCown ◽  
Andrew J. Specht
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Diagnostic Testing ◽  
Clinical Manifestations ◽  
Essential Element ◽  
The Body ◽  
Deficiency Anemia ◽  
Enzyme Systems ◽  
Living Organisms

Iron is an essential element for nearly all living organisms and disruption of iron homeostasis can lead to a number of clinical manifestations. Iron is used in the formation of both hemoglobin and myoglobin, as well as numerous enzyme systems of the body. Disorders of iron in the body include iron deficiency anemia, anemia of inflammatory disease, and iron overload. This article reviews normal iron metabolism, disease syndromes of iron imbalance, diagnostic testing, and treatment of either iron deficiency or excess. Recent advances in diagnosing iron deficiency using reticulocyte indices are reviewed.

scholarly journals Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis

2018 ◽  
Vol 115 (12) ◽  
pp. 3000-3005 ◽  
Author(s):  
Benjamin H. Hudson ◽  
Andrew T. Hale ◽  
Ryan P. Irving ◽  
Shenglan Li ◽  
John D. York
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Reduction ◽  
Genetic Basis ◽  
Iron Homeostasis ◽  
Deficiency Anemia ◽  
Sulfur Assimilation ◽  
Nucleotide Hydrolysis ◽  
Evolutionarily Conserved ◽  
Organismal Development

Sulfur assimilation is an evolutionarily conserved pathway that plays an essential role in cellular and metabolic processes, including sulfation, amino acid biosynthesis, and organismal development. We report that loss of a key enzymatic component of the pathway, bisphosphate 3′-nucleotidase (Bpnt1), in mice, both whole animal and intestine-specific, leads to iron-deficiency anemia. Analysis of mutant enterocytes demonstrates that modulation of their substrate 3′-phosphoadenosine 5′-phosphate (PAP) influences levels of key iron homeostasis factors involved in dietary iron reduction, import and transport, that in part mimic those reported for the loss of hypoxic-induced transcription factor, HIF-2α. Our studies define a genetic basis for iron-deficiency anemia, a molecular approach for rescuing loss of nucleotidase function, and an unanticipated link between nucleotide hydrolysis in the sulfur assimilation pathway and iron homeostasis.

scholarly journals Understanding the Transferrin Receptor and Cellular Iron Deficiency Outside the Erythron

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-42-SCI-42
Author(s):  
Nancy C. Andrews
Keyword(s):  
Iron Deficiency ◽  
Missense Mutation ◽  
Transferrin Receptor ◽  
Iron Uptake ◽  
Clinical Manifestations ◽  
Cell Types ◽  
Conditional Knockout ◽  
Deficiency Anemia ◽  
Transferrin Receptor 1

Our laboratory showed that mouse embryos lacking the classical transferrin receptor, Tfrc, experienced anemia, pericardial effusion and a kinking of the neural tube, but otherwise appeared to be developing normally, suggesting that Tfrc was not needed by most tissues (Levy et al. 1999). Subsequently, we reported that Tfrc was essential for hematopoiesis but seemed to be dispensable in other tissues (Ned et al., 2003). A recent paper showing that a missense mutation in the TFRC internalization motif resulted in immunodeficiency without other clinical manifestations was consistent with this idea (Jabara et al., 2016). Nonetheless, we were not entirely convinced. More than thirty years ago, Larrick and Hyman described a patient with an anti-TFRC autoantibody who suffered from a broader range of clinical problems, suggesting that TFRC might have other roles (Larrick and Hyman, 1984). To help resolve the issue, we developed mice carrying an allele of Tfrc that can be conditionally inactivated, and used Cre/lox-mediated recombination to disrupt that allele in vivo, in several key cell types. We asked two questions: (1) is Tfrc important in those cell types and, if so, (2) what are the cellular consequences of Tfrc loss? We found that some cell types do not need Tfrc but others are highly dependent upon it. Those cell types that depend upon Tfrc generally need it for iron uptake, as expected, with one exception. Tfrc is critically important for normal development of the intestinal epithelium, but our data indicate that its essential role does not involve iron uptake. While surprising in view of our earlier results, the roles of Tfrc that we have unmasked through conditional knockout experiments would not have been apparent prior to the death of global Tfrc knockout embryos in mid-gestation. Nonetheless those roles are important, and our results give insight into why iron deficiency exacerbates heart failure, how muscle iron deficiency leads to disruption of systemic carbon metabolism, and how iron deficiency, rather than iron excess, may play a role in the pathogenesis of neurodegenerative disorders. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396-9. Ned RM, Swat W, Andrews NC. Transferrin receptor 1 is differentially required in lymphocyte development. Blood. 2003;102:3711-8. Jabara HH, Boyden SE, Chou J et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet. 2016;48:74-8. Larrick JW, Hyman ES. Acquired iron-deficiency anemia caused by an antibody against the transferrin receptor. N Engl J Med. 1984;311:214-8. Disclosures Andrews: Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Liver iron sensing and body iron homeostasis

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Chia-Yu Wang ◽  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Inflammatory Diseases ◽  
Genetic Disorders ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Iron Loading ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Supply

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

scholarly journals Treatment of Anemia Progression via Magnetite and Folate Nanoparticles In Vivo

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Hanaa Hussein Elsayed ◽  
Al Sayed A. M. Al-Sherbini ◽  
Eman Elsayed Abd-Elhady ◽  
Kawkab Abd El Aziz. Ahmed
Keyword(s):  
Iron Deficiency ◽  
Public Health Problem ◽  
Negative Control ◽  
Deficiency Anemia ◽  
Iron Oxide Nanoparticle ◽  
Standard Diet ◽  
Global Public Health ◽  
Toxicological Effects ◽  
Loss Of Appetite

Iron deficiency anemia is a major global public health problem. Food fortification with iron (Fe) can be an effective strategy to control iron deficiency. An iron oxide nanoparticle (NP) is a new physical and chemical property form. These properties (small particle size, unique physical properties) make nanoiron a great scientific interest especially in the treatment of anemia. The study aimed to reduce anemia by nanoparticles (NPs). Forty-eight adult female Sprague-Dewily rats were divided into four groups (12 rats each). Group A represented a negative control. Other groups were fed standard diet iron free and three time of require zinc to reach anemic. Group B fed standard diet with ferrous sulfate until the improvement of the situation of anemia or for 8 weeks. Groups C and D were divided into three subgroups; each subgroup was fed a dose from magnetite or folate coated magnetite NPs. Results showed that symptoms of loss of appetite and severe lethargy demonstrate that magnetite and folate-coated magnetite nanoparticles have serious toxicological effects in vivo. Some doses from NPs improve blood picture during 2 weeks but change in histopathology examinations were occur in some groups within 2 weeks. Nanoparticles were considered the toxicological hazards especially the size of less than 54 nm.

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