A Rare Case Of a 2-year-old Boy With Alagille Syndrome and Type 3 Hereditary Hemochromatosis With TFR2 Mutation

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00278.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. G323-G328 ◽

Cited By ~ 32

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.

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

AJP Cell Physiology ◽

10.1152/ajpcell.00492.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. C383-C390 ◽

Cited By ~ 16

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.

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