Genetic Background of Primary Iron Overload Syndromes in Japan

Hayashi, Hisao; Wakusawa, Shinya; Motonishi, Satoshi; Miyamoto, Ken‐ichi; Okada, Hidetoshi; Inagaki, Yasutaka; Ikeda, Takaaki

doi:10.2169/internalmedicine.45.1876

Cited by 35 publications

(35 citation statements)

References 48 publications

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“…Since then, a variety of other TfR2 mutations have been found in Italian patients (Majore et al, 2006; Biasiotto et al, 2008; Gerolami et al, 2008; Radio et al, 2014). Because the most common mutation in HFE is not present in the Japanese population, Japanese patients with HH most frequently have mutations in TfR2 (Hattori et al, 2003; Koyama et al, 2005; Hayashi et al, 2006). Many mutations in TfR2 identified to date fail to give insight into TfR2 function because most mutations result in misfolded proteins that remain in the endoplasmic reticulum (ER; Wallace et al, 2008), where they are presumably degraded by the ER quality control pathway.…”

Section: Disease-causing Mutations In Tfr2mentioning

confidence: 99%

The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body

Worthen

Enns

2014

Front. Pharmacol.

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Fine-tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron sensor, transferrin receptor 2 (TfR2), is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH). With the loss of functional TfR2, the liver produces about 2-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin (Tf) in the bloodstream, and hepatocytes treated with Tf respond with a 2-fold increase in hepcidin expression through stimulation of the bone morphogenetic protein (BMP)-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.

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Section: Disease-causing Mutations In Tfr2mentioning

confidence: 99%

The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body

Worthen

Enns

2014

Front. Pharmacol.

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“…[7][8][9][10][11][12][13][14][15] There have only been a few brief reports of non-HFE hemochromatosis in Asia, which appear to be isolated mutations with most cases around Eastern Asia. [16][17][18] In the Indian subcontinent, reports are even fewer with only 2 cases of type 4 hemochromatosis identified and no cases of JH. 19,20 At present, a difficulty with recognizing hereditary hemochromatosis in some parts of Asia is the presence of hemoglobin disorders such as thalassemia and the resulting secondary iron overload.…”

Section: Introductionmentioning

confidence: 99%

Iron overload in the Asian community

Lok

Merryweather‐Clarke

Viprakasit

et al. 2009

Blood

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“…The same mutation was found in the Huh-7 hepatoma cell line and was shown to prevent the translocation of HFE to the cell surface [88]. In addition, families with various types of HH were sporadically reported from Asian countries, including Japan, China, and Pakistan [67,87,[89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104]. In Japan, mutations in HFE2 (type 2A), TFR2 (type 3), and SLC40A1 (type 4) seem relatively common causes of HH [97].…”

Section: Various Types Of Hhmentioning

confidence: 87%

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Kawabata

2017

Int J Hematol

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Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

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Genetic Background of Primary Iron Overload Syndromes in Japan

Abstract: Abstract

Cited by 35 publications

References 48 publications

The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body

The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body

Iron overload in the Asian community

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

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