scholarly journals Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions

2021 ◽  
Vol 8 ◽  
Author(s):  
Emmanuelle Albalat ◽  
Thibault Cavey ◽  
Patricia Leroyer ◽  
Martine Ropert ◽  
Vincent Balter ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Whole Blood ◽  
Isotope Composition ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Hfe Gene ◽  
Iron Isotope ◽  
Heavy Isotope ◽  
Knock Out

Hereditary hemochromatosis is a genetic iron overload disease related to a mutation within the HFE gene that controls the expression of hepcidin, the master regulator of systemic iron metabolism. The natural stable iron isotope composition in whole blood of control subjects is different from that of hemochromatosis patients and is sensitive to the amount of total iron removed by the phlebotomy treatment. The use of stable isotopes to unravel the pathological mechanisms of iron overload diseases is promising but hampered by the lack of data in organs involved in the iron metabolism. Here, we use Hfe−/− mice, a model of hereditary hemochromatosis, to study the impact of the knock-out on iron isotope compositions of erythrocytes, spleen and liver. Iron concentration increases in liver and red blood cells of Hfe−/− mice compared to controls. The iron stable isotope composition also increases in liver and erythrocytes, consistent with a preferential accumulation of iron heavy isotopes in Hfe−/− mice. In contrast, no difference in the iron concentration nor isotope composition is observed in spleen of Hfe−/− and control mice. Our results in mice suggest that the observed increase of whole blood isotope composition in hemochromatosis human patients does not originate from, but is aggravated by, bloodletting. The subsequent rapid increase of whole blood iron isotope composition of treated hemochromatosis patients is rather due to the release of hepatic heavy isotope-enriched iron than augmented iron dietary absorption. Further research is required to uncover the iron light isotope component that needs to balance the accumulation of hepatic iron heavy isotope, and to better understand the iron isotope fractionation associated to metabolism dysregulation during hereditary hemochromatosis.

Duodenal nonheme iron content correlates with iron stores in mice, but the relationship is altered by Hfe gene knock-out

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3316-3318 ◽  
Author(s):  
Robert J. Simpson ◽  
Edward S. Debnam ◽  
Abas H. Laftah ◽  
Nita Solanky ◽  
Nick Beaumont ◽  
...  
Keyword(s):  
Iron Content ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Nonheme Iron ◽  
Hfe Gene ◽  
Liver Iron ◽  
Knock Out ◽  
Iron Stores ◽  
Knock Out Mice

Abstract Hereditary hemochromatosis is a common iron-loading disorder found in populations of European descent. It has been proposed that mutations causing loss of function of HFE gene result in reduced iron incorporation into immature duodenal crypt cells. These cells then overexpress genes for iron absorption, leading to inappropriate cellular iron balance, a persistent iron deficiency of the duodenal mucosa, and increased iron absorption. The objective was to measure duodenal iron content in Hfe knock-out mice to test whether the mutation causes a persistent decrease in enterocyte iron concentration. In both normal and Hfe knock-out mice, duodenal nonheme iron content was found to correlate with liver iron stores (P < .001, r = 0.643 and 0.551, respectively), and this effect did not depend on dietary iron levels. However, duodenal iron content was reduced in Hfe knock-out mice for any given content of liver iron stores (P < .001).

scholarly journals Discrepancy between Serum Ferritin and Liver Iron Concentration in a Patient with Hereditary Hemochromatosis – The Value of T2* MRI

2020 ◽  
Vol 13 (2) ◽  
pp. 712-715
Author(s):  
Mustafa A. Al-Tikrity ◽  
Mohamed A. Yassin
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Ferritin Level ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Hfe Gene ◽  
Liver Iron Concentration ◽  
C282y Mutation ◽  
Liver Iron ◽  
T2 Mri

Primary hemochromatosis is an inherited disorder, and the homeostatic iron regulator (HFE) gene C282Y mutation is a common cause of hemochromatosis in Europe. We are reporting a case of a 56-year-old female known to have hemochromatosis with the HFE gene C282Y mutation with a serum ferritin level of 482 μg/L who underwent heart and liver T2* MRI which showed no evidence of iron overload – neither in the heart nor in the liver. This indicates that there is a discrepancy between serum ferritin and liver iron concentration by MRI and the superiority of T2* MRI in diagnosis and follow-up of iron overload in patients with hereditary hemochromatosis.

scholarly journals Hemochromatosis: one form of iron-overload diseases

2013 ◽  
Vol 154 (29) ◽  
pp. 1156-1164 ◽  
Author(s):  
Ferenc Szalay
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Clinical Symptoms ◽  
Fetal Liver ◽  
Hereditary Hemochromatosis ◽  
Gene Mutations ◽  
Organ Injury ◽  
Beta Thalassemia ◽  
Hfe Gene ◽  
Kinase Gene

Iron-overload diseases are typically insidious, causing progressive and irreversible organ injury before clinical symptoms develop. Some iron-overload diseases as HFE-associated hemochromatosis and beta-thalassemia are quite common, whereas others are very rare. Early diagnosis is important since iron toxicity can be attenuated or prevented. Significant progress of our knowledge on iron metabolism developed in the past years. We learned a lot about HFE gene mutations, function of ferroportin and hepcidin, the hypoferremia hormone produced by the liver. However, many questions are still open. Special forms of localized iron overload are the Hallervorden-Spatz syndrome and pantothenate kinase gene mutation associated neurodegeneration causing progressive extrapyramidal movement disorders. Neonatal hemochromatosis is a severe systemic iron-overload disorder due to gestational alloimmune liver disease caused by transplacental maternal IgG directed against the fetal liver. This review article gives an overview on iron metabolism and iron-overload disease. Pathomechanism, diagnosis and treatment of hereditary hemochromatosis are discussed. Orv. Hetil., 2013, 154, 1156–1164.

scholarly journals Contributions of β2-microglobulin–dependent molecules and lymphocytes to iron regulation: insights from HfeRag1-/- and β2mRag1-/- double knock-out mice

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2847-2849 ◽  
Author(s):  
Carlos J. Miranda ◽  
Hortence Makui ◽  
Nancy C. Andrews ◽  
Manuela M. Santos
Keyword(s):  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Protein S ◽  
Iron Accumulation ◽  
Iron Regulation ◽  
Hfe Gene ◽  
Knock Out ◽  
Β2 Microglobulin ◽  
Knock Out Mice ◽  
Deficient Mice

Abstract Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a β2-microglobulin (β2m)-associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of β2mRag1-/- double-deficient mice, lacking all β2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with β2m single knock-out mice. To evaluate whether the observed phenotype in β2mRag1-/- mice was due solely to the absence of Hfe or to other β2m-dependent molecules, we generated HfeRag1-/- double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with β2mRag1-/- mice. These results suggest that other β2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity. (Blood. 2004;103: 2847-2849)

Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2841-2843 ◽  
Author(s):  
Gaël Nicolas ◽  
Nancy C. Andrews ◽  
Axel Kahn ◽  
Sophie Vaulont
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Genetic Modifier ◽  
Hereditary Hemochromatosis ◽  
Iron Accumulation ◽  
Hfe Gene ◽  
Type I ◽  
Regulatory Peptide ◽  
Liver Iron ◽  
Very High

Abstract Hereditary hemochromatosis (HH) type I is a disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, its penetrance seems very low. The goal of our study was to determine whether hepcidin, a recently identified iron-regulatory peptide, could be a genetic modifier contributing to the HH phenotype. In mice, deficiency of either HFE (Hfe-/-) or hepcidin (Usf2-/-) is associated with the same pattern of iron overload observed in patients with HH. We intercrossed Hfe-/- and Usf2+/- mice and asked whether hepcidin deficiency increased the iron burden in Hfe-/- mice. Our results showed that, indeed, liver iron accumulation was greater in the Hfe-/-Usf2+/- mice than in mice lacking Hfe alone. This result, in agreement with recent findings in humans, provides a genetic explanation for some variability of the HH phenotype. (Blood. 2004;103: 2841-2843)

scholarly journals Iron age: novel targets for iron overload

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 216-221 ◽  
Author(s):  
Carla Casu ◽  
Stefano Rivella
Keyword(s):  
Iron Overload ◽  
Iron Age ◽  
Iron Metabolism ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Therapeutic Approaches ◽  
Hepcidin Expression ◽  
Beneficial Effects ◽  
Excess Iron ◽  
Major Factors

Abstract Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

Physiologic systemic iron metabolism in mice deficient for duodenal Hfe

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4511-4517 ◽  
Author(s):  
Maja Vujic Spasic ◽  
Judit Kiss ◽  
Thomas Herrmann ◽  
Regina Kessler ◽  
Jens Stolte ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Binding Capacity ◽  
Hereditary Hemochromatosis ◽  
Direct Interaction ◽  
Hfe Gene ◽  
Hepatic Iron ◽  
Primary Role ◽  
Genes Encoding

Abstract Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the “iron hormone” hepcidin which then controls intestinal iron absorption.

Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 39-50
Author(s):  
Gary M. Brittenham ◽  
Günter Weiss ◽  
Pierre Brissot ◽  
Fabrice Lainé ◽  
Anne Guillygomarc'h ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Full Range ◽  
Hereditary Hemochromatosis ◽  
Laboratory Evaluation ◽  
Hfe Gene ◽  
Iron Regulatory Proteins ◽  
Heme Metabolism ◽  
Clinical Consequences ◽  
And Storage

This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage—transferrin, transferrin receptor, and ferritin—have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the “Stimulator of Fe Transport” (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.

Iron Overload in C282Y Heterozygotes: Identification of New Rare HFE Gene Mutants and a Step Strategy for Diagnosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1859-1859
Author(s):  
Patricia Aguilar-Martinez ◽  
Severine Cunat ◽  
Fabienne Becker ◽  
Francois Blanc ◽  
Marlene Nourrit ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Genetic Defect ◽  
Transferrin Saturation ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Exon 2 ◽  
High Iron ◽  
Iron Parameters

Abstract Introduction: Homozygozity for the p.Cys282Tyr (C282Y) mutation of the HFE gene is the main genotype associated with the common form of adult hereditary hemochromatosis. C282Y carriers do not usually develop iron overload, unless they have additional risk factors such as liver diseases, a dysmetabolic syndrome or an associated genetic defect. The commonest is the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele. However, a few rare HFE mutations can be found on the 6th chromosome in trans, some of which are of clinical interest to fully understand the disorder. Patients and Methods: We recently investigated four C282Y carrier patients with unusually high iron parameters, including increased levels of serum ferritin (SF), high transferrin saturation (TS) and high iron liver content measured by MRI. They were males, aged 37, 40, 42, 47 at diagnosis. Two brothers (aged 40 and 42) were referred separately. The HFE genotype, including the determination of the C282Y, H63D and S65C mutations was performed using PCR-RFLP. HFE sequencing was undertaken using the previously described SCA method (1). Sequencing of other genes (namely, HAMP, HJV/HFE2, SLC40A1, TFR2) was possibly performed in a last step using the same method. Results: We identified three rare HFE mutant alleles, two of which are undescribed, in the four studied patients. One patient bore a 13 nucleotide-deletion in exon 6 (c.[1022_1034del13], p.His341_Ala345&gt;LeufsX119), which is predicted to lead to an abnormal, elongated protein. The two brothers had a substitution of the last nucleotide of exon 2 (c.[340G&gt;A], p.Glu114Lys) that may modify the splicing of the 2d intron. The third patient, who bore an insertion of a A in exon 4 (c.[794dupA],p.[trp267LeufsX80]), has already been reported (1). Discussion: A vast majority of C282Y carriers will not develop iron overload and can be reassured. However, a careful step by step strategy at the clinical and genetic levels may allow to correctly identify those patients deserving further investigation. First, clinical examination and the assessment of iron parameters (SF and TS) allow identifying C282Y heterozygotes with an abnormal iron status. Once extrinsic factors such as heavy alcohol intake, virus or a dysmetabolic syndrome have been excluded, MRI is very useful to authenticate a high liver iron content. Second, HFE genotype must first exclude the presence of the H63D mutation. Compound heterozygozity for C282Y and H63D, a very widespread condition in our area, is usually associated with mild iron overload. Third, HFE sequencing can be undertaken and may identify new HFE variants as described here. The two novel mutations, a frameshift modifying the composition and the length of the C terminal end of the HFE protein and a substitution located at the last base of an exon, are likely to lead to an impaired function of HFE in association with the C282Y mutant. However, it is noteworthy that three of the four patients were diagnosed relatively late, after the 4th decade, as it is the case for C282Y homozygotes. Three further unrelated patients are currently under investigation in our laboratory for a similar clinical presentation. Finally, it can be noted that in those patients who will not have a HFE gene mutant identified, analysis of other genes implicated in iron overload must be performed to search for digenism or multigenism. None of our investigated patients had an additional gene abnormality.

Iron Sufficient to Cause Hepatic Fibrosis and Ascites Does Not Cause Cardiac Arrhythmias in the Gerbil

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3834-3834
Author(s):  
Lana Kaiser ◽  
John Davis ◽  
Jon Patterson ◽  
Abby Johnson ◽  
George Bohart ◽  
...  
Keyword(s):  
Heart Rate ◽  
Iron Overload ◽  
Cardiac Arrhythmias ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Liver Weight ◽  
Heart Weight ◽  
Sinus Arrhythmia ◽  
Hepatic Histology ◽  
Morbid Conditions

Abstract Chronic iron overload associated with hereditary hemochromatosis or repeated red cell transfusions is known to cause cardiac failure. Cardiac arrhythmias have been incidentally noted in patients with iron overload, but often times dismissed as being caused by other co-morbid conditions. Studies with iron-loaded gerbils suggest a role for iron in the development of cardiac arrhythmias, however these studies utilized short duration recordings of anesthetized gerbils. Furthermore, we were unable to reproduce these loading protocols without significant morbidity and mortality. Our goal was to characterize iron-induced arrhythmias in the chronically instrumented, untethered, telemetered gerbil. Monitored gerbils were divided into 2 groups: iron-loaded (n=23) and control (n=8). Iron loaded gerbils received iron dextran intraperitoneally at a dose of 1.7 (n=4), 3.0 (n=5) or 6.2 (n=14) g/kg; control gerbils received dextran. Gerbils were weighed and given a physical exam weekly. Electrocardiograms were recorded for 10 seconds every 30 minutes for approximately 6 months (DSI Ponehma) and reviewed daily. Quantitative analysis was completed on 6 iron loaded (6.2g/kg) and 3 control gerbils. Heart rate and intervals were calculated and arrhythmias were characterized and counted. Cardiac and hepatic histology and tissue iron concentration were assessed. All gerbils showed evidence of frequent sinus arrhythmia (more than one episode per hour). However, except for two control gerbils that showed frequent unifocal PVCs, no significant arrhythmias were noted in daily review. There was no difference in heart rate, P duration, PR interval, QRS duration or QT interval between groups. Neither total number of arrhythmias nor arrhythmias per minute were different between groups. One iron-loaded gerbil had a single episode (11 beats) of supraventricular tachycardia. Two iron-loaded gerbils had PVCs, one had only a single beat and the other had 9 unifocal PVCs over the duration of the study. Iron-loaded gerbils rarely showed other arrhythmias One control gerbil had 260 unifocal PVCs over the duration of the study. Other arrhythmias were noted rarely. Body weight and heart weight was not different between groups, while liver weight increased with increasing iron dose. Cardiac and hepatic iron were significantly increased in iron loaded gerbils when compared to control. Liver weight increased as iron dose increased. Seven of 14 gerbils loaded to 6.2 g/kg developed ascites as assessed both by physical examination and necropsy. We conclude that an iron load sufficient to cause clinical liver disease does not, in the absence of co-morbid conditions, cause cardiac arrhythmias in the gerbil model of iron overload. This suggests that iron alone is insufficient to cause cardiac arrhythmias.

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