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Matthew B Lanktree, Bekim Sadikovic, John S Waye, Alexander Levstik, Bruce B Lanktree, Jovana Yudin, Mark A Crowther, Guillaume Pare, Paul C Adams
BACKGROUND: Next-generation sequencing of an iron metabolism gene panel could identify pathogenic mutations, improving on standard hemochromatosis genetic testing and providing a molecular diagnosis in patients with suspected iron overload. METHODS: A next-generation sequencing panel of 15 genes with known roles in iron metabolism was constructed. 190 patients were sequenced: 94 from a tertiary hemochromatosis clinic, and 96 submitted for HFE testing with biochemical evidence of iron overload [elevated ferritin (>450 μg/L) or transferrin saturation (>55%)] obtained from a chart review...
October 18, 2016: European Journal of Haematology
Kaczorowska-Hac Barbara, Luszczyk Marcin, Antosiewicz Jedrzej, Ziolkowski Wieslaw, Adamkiewicz-Drozynska Elzbieta, Mysliwiec Malgorzata, Milosz Ewa, Kaczor Jan Jacek
The molecular mechanism that regulates iron homeostasis is based on a network of signals, which reflect on the iron requirements of the body. Hereditary hemochromatosis is a heterogenic metabolic syndrome which is due to unchecked transfer of iron into the bloodstream and its toxic effects on parenchymatous organs. It is caused by the mutation of genes that encode proteins that help hepcidin to monitor serum iron. These proteins include the human hemochromatosis protein -HFE, transferrin-receptor 2, hemojuvelin in rare instances, and ferroportin...
August 24, 2016: Annals of Hematology
Juliana Frossard Ribeiro Mendes, Egle Machado de Almeida Siqueira, João Gabriel Marques de Brito E Silva, Sandra Fernandes Arruda
BACKGROUND: Considering that vitamin A deficiency modulates hepcidin expression and consequently affects iron metabolism, we evaluated the effect of vitamin A deficiency in the expression of genes involved in the hemojuvelin (HJV)-bone morphogenetic protein 6 (BMP6)-small mothers against decapentaplegic protein (SMAD) signaling pathway. METHODS: Male Wistar rats were treated: control AIN-93G diet (CT), vitamin A-deficient diet (VAD), iron-deficient diet (FeD), vitamin A- and iron-deficient diet (VAFeD), or 12 mg all-trans retinoic acid (atRA)/kg diet...
2016: Genes & Nutrition
Halie K Miller, Leah Schwiesow, Winnie Au-Yeung, Victoria Auerbuch
The iron overload disorder hereditary hemochromatosis (HH) predisposes humans to serious disseminated infection with pathogenic Yersinia as well as several other pathogens. Recently, we showed that the iron-sulfur cluster coordinating transcription factor IscR is required for type III secretion in Y. pseudotuberculosis by direct control of the T3SS master regulator LcrF. In E. coli and Yersinia, IscR levels are predicted to be regulated by iron bioavailability, oxygen tension, and oxidative stress, such that iron depletion should lead to increased IscR levels...
2016: Frontiers in Cellular and Infection Microbiology
Elisa Ferro, Angela Di Pietro, Giuseppa Visalli, Basilia Piraino, Carmelo Salpietro, Maria Angela La Rosa
OBJECTIVE: The hemojuvelin-bone morphogenetic protein axis is the principal iron-dependent mechanism of hepcidin regulation. The determination of soluble hemojuvelin (sHJV) levels could allow for a better understanding of the pathophysiological mechanisms of hepcidin regulation in thalassaemia. METHOD: We have assessed sHJV in 45 transfused and 15 untransfused thalassaemic patients in comparison with 15 healthy subjects, evaluating its relationships with some parameters of iron overload, anaemia and erythropoiesis...
July 21, 2016: European Journal of Haematology
Sandra Ribeiro, Patrícia Garrido, João Fernandes, Susana Rocha, Petronila Rocha-Pereira, Elísio Costa, Luís Belo, Flávio Reis, Alice Santos-Silva
The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600IU/kgbody weight/week), 3 times per week, during 3weeks. Hematological and iron data were evaluated...
July 2016: Blood Cells, Molecules & Diseases
Heinz Zoller, Benjamin Henninger
Hemochromatosis is a common cause of chronic liver disease and HFE genotyping allows decisive and non-invasive diagnosis. Molecular and clinical genetic studies have led to the identification of genes other than HFE in patients with inherited diseases associated with increased hepatic iron storage that can cause hemochromatosis, which adds complexity to a diagnostic approach to patients with suspected hemochromatosis. Despite major advances in genetics, hepatic iron quantification by non-invasive methods therefore remains the key to the diagnosis of hemochromatosis...
2016: Digestive Diseases
Simeng Chen, Teng Feng, Maja Vujić Spasić, Sandro Altamura, Katja Breitkopf-Heinlein, Jutta Altenöder, Thomas S Weiss, Steven Dooley, Martina U Muckenthaler
The hepatic hormone hepcidin is the master regulator of systemic iron homeostasis. Its expression level is adjusted to alterations in iron levels, inflammatory cues, and iron requirements for erythropoiesis. Bone morphogenetic protein 6 (BMP6) contributes to the iron-dependent control of hepcidin. In addition, TGF-β1 may stimulate hepcidin mRNA expression in murine hepatocytes and human leukocytes. However, receptors and downstream signaling proteins involved in TGF-β1-induced hepcidin expression are still unclear...
June 17, 2016: Journal of Biological Chemistry
Ningning Zhao, Julia E Maxson, Richard H Zhang, Mastura Wahedi, Caroline A Enns, An-Sheng Zhang
Hemojuvelin (HJV) regulates iron homeostasis by direct interaction with bone morphogenetic protein (BMP) ligands to induce hepcidin expression through the BMP signaling pathway in the liver. Crystallography studies indicate that HJV can simultaneously bind to both BMP2 and the ubiquitously expressed cell surface receptor neogenin. However, the role of the neogenin-HJV interaction in the function of HJV is unknown. Here we identify a mutation in HJV that specifically lowers its interaction with neogenin. Expression of this mutant Hjv in the liver of Hjv(-/-) mice dramatically attenuated its induction of BMP signaling and hepcidin mRNA, suggesting that interaction with neogenin is critical for the iron regulatory function of HJV...
June 3, 2016: Journal of Biological Chemistry
Pachiappan Arjunan, Jaya P Gnanaprakasam, Sudha Ananth, Michelle A Romej, Veeranan-Karmegam Rajalakshmi, Puttur D Prasad, Pamela M Martin, Mariappan Gurusamy, Muthusamy Thangaraju, Yangzom D Bhutia, Vadivel Ganapathy
PURPOSE: Hemochromatosis, an iron-overload disease, occurs as adult and juvenile types. Mutations in hemojuvelin (HJV), an iron-regulatory protein and a bone morphogenetic protein (BMP) coreceptor, underlie most of the juvenile type. Hjv(-/-) mice accumulate excess iron in retina and exhibit aberrant vascularization and angiomas. A succinate receptor, GPR91, is pro-angiogenic in retina. We hypothesized that Hjv(-/-) retinas have increased BMP signaling and increased GPR91 expression as the basis of angiomas...
April 2016: Investigative Ophthalmology & Visual Science
Jingqi Liu, Chunwen Pu, Lang Lang, Liang Qiao, Mohanud Abukar Haji Abdullahi, Chunmeng Jiang
Hereditary hemochromatosis (HH) is an inherited iron overload disorder characterized by normal iron-driven erythropoiesis and abnormal iron metabolism, leading to excess iron deposited in parenchymal cells of liver, heart, and endocrine glands. Iron hormone, hepcidin, plays a critical role in iron homeostasis through interaction with ferroportin (FPN), a major cellular iron exporter. Hepcidin is encoded by hepcidin antimicrobial peptide (HAMP). Mutations in hepcidin and any genes that regulate the biology of hepcidin, including hemochromatosis genes (HFE), Hemojuvelin (HJV), transferring receptor 2 (TFR2) and FPN, result in hemochromatosis...
August 2016: Histology and Histopathology
Lucija Šimetić, Lada Zibar
Hepcidin is a small peptide with a critical role in cellular iron homeostasis, as it regulates utilization of stored iron and antimicrobial defense in inflammation (bacterial and fungal). Since it was isolated in 2000, and especially in the last decade, numerous studies aimed to evaluate the clinical use of plasma and urine hepcidin as a marker of anemia, especially anemia of chronic disease and post-transplant anemia (PTA). Hepcidin regulation is delicately tuned by two inflammatory pathways activated by interleukin-6 (IL-6) and bone morphogenic proteins (BMPs) and iron regulated pathway sensitive to circulating transferin-iron (TR-Fe) complex...
2016: Biochemia Medica: časopis Hrvatskoga Društva Medicinskih Biokemičara
Suzana Kovac, Preethne Böser, Yifang Cui, Dunja Ferring-Appel, Daniela Casarrubea, Lili Huang, Emma Fung, Andreas Popp, Bernhard K Mueller, Matthias W Hentze
No abstract text is available yet for this article.
May 2016: Haematologica
P Przybylowski, G Wasilewski, K Golabek, H Bachorzewska-Gajewska, S Dobrzycki, E Koc-Zorawska, J Malyszko
BACKGROUND: Anemia is relatively common in patients with heart failure and heart transplant recipients. Both absolute and functional iron deficiency may contribute to the anemia in these populations. Functional iron deficiency (defined as ferritin greater than 200 ng/mL with TSAT (Transferrin saturation) less than 20%) is characterized by the presence of adequate iron stores as defined by conventional criteria, but with insufficient iron mobilization to adequately support. The aim of this study was to determine prevalence of absolute and functional iron deficiency in patients with heart failure (n = 269) and after heart transplantation (n = 130) and their relation to parameters of iron status and inflammation...
January 2016: Transplantation Proceedings
Jana Frýdlová, Petr Přikryl, Jaroslav Truksa, Lucas L Falke, Xin Du, Iuliia Gurieva, Martin Vokurka, Jan Krijt
Matriptase-2 (TMPRSS6) is an important negative regulator of hepcidin expression; however, the effects of iron overload or accelerated erythropoiesis on liver TMPRSS6 protein content in vivo are largely unknown. We determined TMPRSS6 protein content in plasma membrane-enriched fractions of liver homogenates by immunoblotting, using a commercial antibody raised against the catalytic domain of TMPRSS6. Plasma membrane-enriched fractions were obtained by centrifugation at 3000 g and washing. TMPRSS6 was detected in the 3000 g fraction as a 120 kDa full-length protein in both mice and rats...
2016: PloS One
Susanna Canali, Amanda B Core, Kimberly B Zumbrennen-Bullough, Maria Merkulova, Chia-Yu Wang, Alan L Schneyer, Antonello Pietrangelo, Jodie L Babitt
Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6...
March 2016: Endocrinology
(no author information available yet)
This article has been retracted at the request of the authors.
November 2015: Journal of Veterinary Medical Science
Pierre Brissot, Olivier Loréal
Body iron has a very close relationship with the liver. Physiologically, the liver synthesizes transferrin, in charge of blood iron transport; ceruloplasmin, acting through its ferroxidase activity; and hepcidin, the master regulator of systemic iron. It also stores iron inside ferritin and serves as an iron reservoir, both protecting the cell from free iron toxicity and ensuring iron delivery to the body whenever needed. The liver is first in line for receiving iron from the gut and the spleen, and is, therefore, highly exposed to iron overload when plasma iron is in excess, especially through its high affinity for plasma non-transferrin bound iron...
February 2016: Journal of Hepatology
Salih Boga, Huseyin Alkim, Canan Alkim, Ali Riza Koksal, Mehmet Bayram, Muveddet Banu Yilmaz Ozguven, Sebnem Tekin Neijmann
BACKGROUND AND AIMS: Mild iron overload is frequently reported in patients with nonalcoholic fatty liver disease (NAFLD). Hepcidin is the master iron-regulatory peptide and hemojuvelin (HJV) is the key regulator of iron-dependent secretion of hepcidin. The aims of this study were to evaluate serum HJV and hepcidin levels in patients with biopsy-proven NAFLD with and without hepatic iron overload, and to identify potential associations of HJV and hepcidin with the clinical characteristics of the patients enrolled...
September 2015: Journal of Gastrointestinal and Liver Diseases: JGLD
Benedikt Schaefer, David Haschka, Armin Finkenstedt, Britt-Sabina Petersen, Igor Theurl, Benjamin Henninger, Andreas R Janecke, Chia-Yu Wang, Herbert Y Lin, Lothar Veits, Wolfgang Vogel, Günter Weiss, Andre Franke, Heinz Zoller
Liver disease due to alpha-1-antitrypsin deficiency (A1ATD) is associated with hepatic iron overload in a subgroup of patients. The underlying cause for this association is unknown. The aim of the present study was to define the genetics of this correlation and the effect of alpha-1-antitrypsin (A1AT) on the expression of the iron hormone hepcidin. Full exome and candidate gene sequencing were carried out in a family with A1ATD and hepatic iron overload. Regulation of hepcidin expression by A1AT was studied in primary murine hepatocytes...
November 1, 2015: Human Molecular Genetics
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