scholarly journals Functional consequences of transferrin receptor‐2 mutations causing hereditary hemochromatosis type 3

2015 ◽  
Vol 3 (3) ◽  
pp. 221-232 ◽  
Author(s):  
Ricky Joshi ◽  
Maya Shvartsman ◽  
Erica Morán ◽  
Sergi Lois ◽  
Jessica Aranda ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Hereditary Hemochromatosis ◽  
Functional Consequences ◽  
Type 3 ◽  
Transferrin Receptor 2

Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

2008 ◽  
Vol 294 (2) ◽  
pp. C383-C390 ◽  
Author(s):  
Daniel F. Wallace ◽  
Lesa Summerville ◽  
Emily M. Crampton ◽  
V. Nathan Subramaniam
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Wild Type ◽  
Mouse Liver Cell ◽  
Functional Consequences ◽  
Consequences Of Disease ◽  
Type 3 ◽  
Mutant Forms ◽  
Transferrin Receptor 2

Transferrin receptor 2 (TfR2), a homologue of transferrin receptor 1 (TfR1), is a key molecule involved in the regulation of iron homeostasis. Mutations in TfR2 result in iron overload with similar features to HFE-associated hereditary hemochromatosis. The precise role of TfR2 in iron metabolism and the functional consequences of disease-causing mutations have not been fully determined. We have expressed wild-type and various mutant forms of TfR2 that are associated with human disease in a mouse liver cell line. Intracellular and surface analysis shows that all the TfR2 mutations analyzed cause the intracellular retention of the protein in the endoplasmic reticulum, whereas the wild-type protein is expressed in endocytic structures and at the cell surface. Our results indicate that the majority of mutations that cause type 3 hereditary hemochromatosis are a consequence of the defective localization of the protein.

scholarly journals The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value

2018 ◽  
Vol 11 (4) ◽  
pp. 115 ◽  
Author(s):  
Antonella Roetto ◽  
Mariarosa Mezzanotte ◽  
Rosa Pellegrino
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Iron Regulation ◽  
Role Taking ◽  
Therapeutic Value ◽  
Living Organisms ◽  
Type 3 ◽  
Functional Versatility ◽  
Transferrin Receptor 2

Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in TFR2 gene are responsible for type 3 hereditary hemochromatosis (HFE3), a genetically heterogeneous disease characterized by systemic iron overload. It has been recently pointed out that Hepc production and iron regulation could be exerted also in tissues other than liver, and that Tfr2 has an extrahepatic role in iron metabolism as well. This review summarizes all the most recent data on Tfr2 extrahepatic role, taking into account the putative distinct roles of the two main Tfr2 isoforms, Tfr2α and Tfr2β. Representing Hepc modulation an effective approach to correct iron balance impairment in common human diseases, and with Tfr2 being one of its regulators, it would be worthwhile to envisage Tfr2 as a therapeutic target.

Novel mutation in the Transferrin receptor-2 in a patient with Hereditary Hemochromatosis type 3

Meta Gene ◽  
2017 ◽  
Vol 14 ◽  
pp. 30-32
Author(s):  
Hanadi Achi ◽  
Nour Moukalled ◽  
Rami Mahfouz ◽  
Alberto Piperno ◽  
Ali Taher
Keyword(s):  
Transferrin Receptor ◽  
Novel Mutation ◽  
Hereditary Hemochromatosis ◽  
Type 3 ◽  
Transferrin Receptor 2

scholarly journals Expression of hepcidin and other iron-related genes in type 3 hemochromatosis due to a novel mutation in transferrin receptor-2

Haematologica ◽  
2009 ◽  
Vol 94 (2) ◽  
pp. 276-279 ◽  
Author(s):  
S. Pelucchi ◽  
R. Mariani ◽  
P. Trombini ◽  
S. Coletti ◽  
M. Pozzi ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Novel Mutation ◽  
Type 3 ◽  
Transferrin Receptor 2

Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3

2007 ◽  
Vol 292 (1) ◽  
pp. G323-G328 ◽  
Author(s):  
S. F. Drake ◽  
E. H. Morgan ◽  
C. E. Herbison ◽  
R. Delima ◽  
R. M. Graham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Transferrin Receptor ◽  
Mutant Mouse ◽  
Hereditary Hemochromatosis ◽  
Mutant Mice ◽  
Wild Type ◽  
Hepcidin Expression ◽  
Fe Uptake ◽  
Type 3

Hereditary hemochromatosis type 3 is an iron (Fe)-overload disorder caused by mutations in transferrin receptor 2 (TfR2). TfR2 is expressed highly in the liver and regulates Fe metabolism. The aim of this study was to investigate duodenal Fe absorption and hepatic Fe uptake in a TfR2 (Y245X) mutant mouse model of hereditary hemochromatosis type 3. Duodenal Fe absorption and hepatic Fe uptake were measured in vivo by 59Fe-labeled ascorbate in TfR2 mutant mice, wild-type mice, and Fe-loaded wild-type mice (2% dietary carbonyl Fe). Gene expression was measured by real-time RT-PCR. Liver nonheme Fe concentration increased progressively with age in TfR2 mutant mice compared with wild-type mice. Fe absorption (both duodenal Fe uptake and transfer) was increased in TfR2 mutant mice compared with wild-type mice. Likewise, expression of genes participating in duodenal Fe uptake ( Dcytb, DMT1) and transfer (ferroportin) were increased in TfR2 mutant mice. Nearly all of the absorbed Fe was taken up rapidly by the liver. Despite hepatic Fe loading, hepcidin expression was decreased in TfR2 mutant mice compared with wild-type mice. Even when compared with Fe-loaded wild-type mice, TfR2 mutant mice had increased Fe absorption, increased duodenal Fe transport gene expression, increased liver Fe uptake, and decreased liver hepcidin expression. In conclusion, despite systemic Fe loading, Fe absorption and liver Fe uptake were increased in TfR2 mutant mice in association with decreased expression of hepcidin. These findings support a model in which TfR2 is a sensor of Fe status and regulates duodenal Fe absorption and liver Fe uptake.

Diferric transferrin regulates transferrin receptor 2 protein stability

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4287-4293 ◽  
Author(s):  
Martha B. Johnson ◽  
Caroline A. Enns
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Transmembrane Protein ◽  
Hereditary Hemochromatosis ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Diferric Transferrin ◽  
In Cells ◽  
Transferrin Receptor 2

Abstract Transferrin receptor 2 (TfR2) is a type 2 transmembrane protein expressed in hepatocytes that binds iron-bound transferrin (Tf). Mutations in TfR2 cause one form of hereditary hemochromatosis, a disease in which excessive absorption of dietary iron can lead to liver cirrhosis, diabetes, arthritis, and heart failure. The function of TfR2 in iron homeostasis is unknown. We have studied the regulation of TfR2 in HepG2 cells. Western blot analysis shows that TfR2 increases in a time- and dose-dependent manner after diferric Tf is added to the culture medium. In cells exposed to diferric Tf, the amount of TfR2 returns to control levels within 8 hours after the removal of diferric Tf from the medium. However, TfR2 does not increase when non–Tf-bound iron (FeNTA) or apo Tf is added to the medium. The response to diferric Tf appears to be hepatocyte specific. Real-time quantitative reverse transcription–polymerase chain reaction (qRT-PCR) analysis shows that TfR2 mRNA levels do not change in cells exposed to diferric Tf. Rather, the increase in TfR2 is attributed to an increase in the half-life of TfR2 protein in cells exposed to diferric Tf. Our results support a role for TfR2 in monitoring iron levels by sensing changes in the concentration of diferric Tf.

scholarly journals Interaction of the Hereditary Hemochromatosis Protein HFE with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

2009 ◽  
Vol 9 (3) ◽  
pp. 217-227 ◽  
Author(s):  
Junwei Gao ◽  
Juxing Chen ◽  
Maxwell Kramer ◽  
Hidekazu Tsukamoto ◽  
An-Sheng Zhang ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Hereditary Hemochromatosis ◽  
Hepcidin Expression ◽  
Transferrin Receptor 2

Blunted hepcidin response to inflammation in the absence of Hfe and transferrin receptor 2

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2960-2966 ◽  
Author(s):  
Daniel F. Wallace ◽  
Cameron J. McDonald ◽  
Lesa Ostini ◽  
V. Nathan Subramaniam
Keyword(s):  
Transferrin Receptor ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Homeostatic Regulation ◽  
Wild Type ◽  
Regulatory Peptide ◽  
Basal Expression ◽  
Low Levels ◽  
Transferrin Receptor 2

AbstractThe induction of the iron-regulatory peptide hepcidin by proinflammatory cytokines is thought to result in the withholding of iron from invading pathogens. Hfe and transferrin receptor 2 (Tfr2) are involved in the homeostatic regulation of hepcidin and their disruption causes hereditary hemochromatosis (HH). To determine whether either Hfe or Tfr2 is involved in the inflammatory pathway regulating hepcidin, we analyzed the effect of inflammation in 3 mouse models of HH. The inflammatory response and indicators of iron homeostasis were measured in wild-type, Hfe−/−, Tfr2−/−, and Hfe−/−/Tfr2−/− mice injected with lipopolysaccharide (LPS). The administration of LPS significantly reduced serum iron in wild-type and Hfe−/− mice, with smaller reductions in Tfr2−/− and Hfe−/−/Tfr2−/− mice. Low basal levels of hepcidin in the Hfe−/−/Tfr2−/− mice were increased in response to LPS, but remained significantly lower than in the other strains of mice. These results suggest that despite the absence of Hfe and Tfr2, hepcidin is responsive to inflammation; however, the low basal expression and subsequent low levels of circulating hepcidin are insufficient to reduce serum iron effectively. This suggests that in HH, the iron-withholding response to invading pathogens may be inadequate, and this is especially the case in the absence of both Hfe and Tfr2.

scholarly journals The Effect of the Flavonol Rutin on Serum and Liver Iron Content in a Genetic Mouse Model of Iron Overload

2021 ◽  
Author(s):  
Zachary Hawula ◽  
Eriza Secondes ◽  
Daniel Wallace ◽  
Gautam Rishi ◽  
V. Nathan Subramaniam
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Binding Capacity ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Loading ◽  
Genetic Mouse Model ◽  
Transferrin Receptor 2

The flavonol rutin has been shown to possess antioxidant and iron chelating properties in vitro and in vivo. These dual properties are beneficial as therapeutic options to reduce iron accumulation and the generation of reactive oxygen species resultant from excess free iron. The effect of rutin on iron metabolism has been limited to studies performed in wild type mice either injected or fed high iron diets. The effect of rutin on iron overload caused by genetic dysregulation of iron homeostasis has not yet been investigated. In this study we examined the effect of rutin treatment on tissue iron loading in a genetic mouse model of iron overload, which mirrors the iron loading associated with Type 3 hereditary hemochromatosis patients who have a defect in Transferrin Receptor 2. Male Transferrin Receptor 2 knockout mice were administered rutin via oral gavage for 21 continuous days. Following treatment, iron levels in serum, liver, duodenum, and spleen were assessed. In addition, hepatic ferritin protein levels were determined by western blotting, and expression of iron homeostasis genes by quantitative real-time PCR. Rutin treatment resulted in a significant reduction in hepatic ferritin protein expression and serum transferrin saturation. In addition, trends towards decreased iron levels in the liver and serum, and increased serum unsaturated iron binding capacity were observed. This is the first study to explore the utility of rutin as a potential iron chelator and therapeutic in an animal model of genetic iron overload.

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