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1.  Age-Dependent Retinal Iron Accumulation and Degeneration in Hepcidin Knockout Mice 
Hepcidin is an iron regulatory hormone expressed in the retina. In the present study, evidence from mice and tissue culture suggest that hepcidin is upregulated in response to increased retinal iron levels and normally serves to prevent retinal iron excess.
Purpose.
Iron dysregulation can cause retinal disease, yet retinal iron regulatory mechanisms are incompletely understood. The peptide hormone hepcidin (Hepc) limits iron uptake from the intestine by triggering degradation of the iron transporter ferroportin (Fpn). Given that Hepc is expressed in the retina and Fpn is expressed in cells constituting the blood-retinal barrier, the authors tested whether the retina may produce Hepc to limit retinal iron import.
Methods.
Retinas of Hepc−/− mice were analyzed by histology, autofluorescence spectral analysis, atomic absorption spectrophotometry, Perls' iron stain, and immunofluorescence to assess iron-handling proteins. Retinal Hepc mRNA was evaluated through qPCR after intravitreal iron injection. Mechanisms of retinal Hepc upregulation were tested by Western blot analysis. A retinal capillary endothelial cell culture system was used to assess the effect of exogenous Hepc on Fpn.
Results.
Hepc−/− mice experienced age-dependent increases in retinal iron followed by retinal degeneration with autofluorescent RPE, photoreceptor death, and subretinal neovascularization. Hepc−/− mice had increased Fpn immunoreactivity in vascular endothelial cells. Conversely, in cultured retinal capillary endothelial cells, exogenous Hepc decreased both Fpn levels and iron transport. The retina can sense increased iron levels, upregulating Hepc after phosphorylation of extracellular signal regulated kinases.
Conclusions.
These findings indicate that Hepc is essential for retinal iron regulation. In the absence of Hepc, retinal degeneration occurs. Increases in Hepc mRNA levels after intravitreal iron injection combined with Hepc-mediated decreases in iron export from cultured retinal capillary endothelial cells suggest that the retina may use Hepc for its tissue-specific iron regulation.
doi:10.1167/iovs.10-6113
PMCID: PMC3053271  PMID: 20811044
2.  Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin 
PLoS Genetics  2013;9(4):e1003408.
Ferroportin (FPN) is the only known cellular iron exporter in mammalian cells and plays a critical role in the maintenance of both cellular and systemic iron balance. During iron deprivation, the translation of FPN is repressed by iron regulatory proteins (IRPs), which bind to the 5′ untranslated region (UTR), to reduce iron export and preserve cellular iron. Here, we report a novel iron-responsive mechanism for the post-transcriptional regulation of FPN, mediated by miR-485-3p, which is induced during iron deficiency and represses FPN expression by directly targeting the FPN 3′UTR. The overexpression of miR-485-3p represses FPN expression and leads to increased cellular ferritin levels, consistent with increased cellular iron. Conversely, both inhibition of miR-485-3p activity and mutation of the miR-485-3p target sites on the FPN 3′UTR are able to relieve FPN repression and lead to decreased cellular iron levels. Together, these findings support a model that includes both IRPs and microRNAs as iron-responsive post-transcriptional regulators of FPN. The involvement of microRNA in the iron-responsive regulation of FPN offers additional stability and fine-tuning of iron homeostasis within different cellular contexts. MiR-485-3p-mediated repression of FPN may also offer a novel potential therapeutic mechanism for circumventing hepcidin-resistant mechanisms responsible for some iron overload diseases.
Author Summary
Cellular iron homeostasis is maintained by a sophisticated system that responds to iron levels and coordinates the expression of targets important for balancing iron export and uptake with intracellular storage and utilization. Ferroportin is the only known cellular iron exporter in mammalian cells and plays a critical role in both cellular and systemic iron balance. Thus the ability to regulate cellular iron export is of great interest in the search for therapeutic strategies to control dysregulated iron homeostasis, iron overload disorders, and conditions affected by cellular iron concentrations such as antimicrobial resistance. During iron deprivation, repression of ferroportin levels reduces iron export and preserves cellular iron. Ferroportin translation is known to be repressed by iron regulatory proteins that bind to the 5′UTR, yet alternative mechanisms that can post-transcriptionally regulate ferroportin have not been previously reported. Here, we find that miR-485-3p is induced during iron deficiency and represses ferroportin by directly targeting its 3′UTR, and further experimental evidence supports a model that includes both iron regulatory proteins and microRNAs as post-transcriptional regulators of ferroportin. These findings demonstrate a novel role for microRNAs in the cellular response to iron deficiency and can have therapeutic implications for various diseases of iron homeostasis.
doi:10.1371/journal.pgen.1003408
PMCID: PMC3616902  PMID: 23593016
3.  Association of CD58 Polymorphism with Multiple Sclerosis and Response to Interferon ß Therapy in A Subset of Iranian Population 
Cell Journal (Yakhteh)  2015;16(4):506-513.
Objective
Multiple sclerosis (MS) is one of the leading neurodegenerative causes of physical disability world-wide. Genetic aberrations of autoimmunity pathway components have been demonstrated to significantly influence MS development. Cluster of Differentiation 58 (CD58) is pertained to a group of genes which had been assayed in several recent association studies. Given the significance of CD58 in modulation of T regulatory cells that control autoimmune responses, the present study was conducted to investigate the frequency of rs12044852 polymorphism and its effect on the outcome of interferon beta (IFN-β) therapy in a subset of Iranian MS patients.
Materials and Methods
Two hundred MS patients and equal number of healthy controls were recruited to be genotyped in an experimental case-control based study through polymerase chain reaction using specific sequence primers (PCR-SSP). Relapsing remitting multiple sclerosis (RRMS) patients administered IFN-β therapy were followed up with clinical visits every three months up to two years. The mean of multiple sclerosis severity score (MSSS) and expanded disability status scale (EDSS) were measured to monitor the change in severity of MS in response to IFN-β therapy. Pearson’s Chi-square and analysis of variance (ANOVA) tests were the main statistical methods used in this study.
Results
Strong association was found between the CC genotype and onset of MS (p=0.001, OR=2.22). However, there was no association between rs12044852 and various classifications and severity of MS. Pharmacogenetics-based analysis indicated that carriers of CC genotype had the highest MSSS score compared to others, implying a negative impact of rs12044852 on response to IFN-β therapy.
Conclusion
Taken together, our findings revealed the critical effect of rs12044852 polymorphism of CD58 on the progression of MS disease. This indicates that genotyping of MS patients may expedite achieving personalized medical management of MS patients.
PMCID: PMC4297489
Multiple Sclerosis; CD58; Polymorphism; Interferon β; Response
4.  Computational Modeling and Analysis of Iron Release from Macrophages 
PLoS Computational Biology  2014;10(7):e1003701.
A major process of iron homeostasis in whole-body iron metabolism is the release of iron from the macrophages of the reticuloendothelial system. Macrophages recognize and phagocytose senescent or damaged erythrocytes. Then, they process the heme iron, which is returned to the circulation for reutilization by red blood cell precursors during erythropoiesis. The amount of iron released, compared to the amount shunted for storage as ferritin, is greater during iron deficiency. A currently accepted model of iron release assumes a passive-gradient with free diffusion of intracellular labile iron (Fe2+) through ferroportin (FPN), the transporter on the plasma membrane. Outside the cell, a multi-copper ferroxidase, ceruloplasmin (Cp), oxidizes ferrous to ferric ion. Apo-transferrin (Tf), the primary carrier of soluble iron in the plasma, binds ferric ion to form mono-ferric and di-ferric transferrin. According to the passive-gradient model, the removal of ferrous ion from the site of release sustains the gradient that maintains the iron release. Subcellular localization of FPN, however, indicates that the role of FPN may be more complex. By experiments and mathematical modeling, we have investigated the detailed mechanism of iron release from macrophages focusing on the roles of the Cp, FPN and apo-Tf. The passive-gradient model is quantitatively analyzed using a mathematical model for the first time. A comparison of experimental data with model simulations shows that the passive-gradient model cannot explain macrophage iron release. However, a facilitated-transport model associated with FPN can explain the iron release mechanism. According to the facilitated-transport model, intracellular FPN carries labile iron to the macrophage membrane. Extracellular Cp accelerates the oxidation of ferrous ion bound to FPN. Apo-Tf in the extracellular environment binds to the oxidized ferrous ion, completing the release process. Facilitated-transport model can correctly predict cellular iron efflux and is essential for physiologically relevant whole-body model of iron metabolism.
Author Summary
Iron metabolism is an important physiological phenomenon essential for sustaining life. There is a tight regulation of iron levels in humans and both deficiency and overload can lead to disorders such as anemia and hemochromatosis. Recycling of iron in human body via macrophage iron release is crucial to maintain healthy iron levels. However, a computational model is needed to quantitatively analyze the mechanism underlying a key process in iron homeostasis, which is the release of iron from the macrophages. Using mechanistic, mathematical models to simulate experimental data, we found a novel mechanism by which macrophages release iron. A comparison of experimental data with model simulations shows that a currently accepted passive-gradient mechanism cannot represent the iron-release process from macrophages. However, our model with a facilitated-transport mechanism associated with ferroportin (only known protein for iron export) accurately reproduces the iron release process. This model quantifies for the first time the detailed molecular mechanism associated with iron transport via ferroportin. This quantitative predictive model of cellular iron efflux is essential for physiologically relevant simulation of whole-body model of iron metabolism in healthy and disease states.
doi:10.1371/journal.pcbi.1003701
PMCID: PMC4083485  PMID: 24991925
5.  The Oral Iron Chelator Deferiprone Protects Against Systemic Iron Overload–Induced Retinal Degeneration in Hepcidin Knockout Mice 
Purpose.
To investigate the retinal-protective effects of the oral iron chelator deferiprone (DFP) in mice lacking the iron regulatory hormone hepcidin (Hepc). These Hepc knockout (KO) mice have age-dependent systemic and retinal iron accumulation leading to retinal degeneration.
Methods.
Hepc KO mice were given DFP in drinking water from age 6 to 18 months. They were then compared to Hepc KO mice not receiving DFP by fundus imaging, electroretinography (ERG), histology, immunofluorescence, and quantitative PCR to investigate the protective effect of DFP against retinal and retinal pigment epithelial (RPE) degeneration.
Results.
In Hepc KO mice, DFP diminished RPE depigmentation and autofluorescence on fundus imaging. Autofluorescence in the RPE layer in cryosections was significantly diminished by DFP, consistent with the fundus images. Immunolabeling with L-ferritin and transferrin receptor antibodies showed a decreased signal for L-ferritin in the inner retina and RPE cells and an increased signal for transferrin receptor in the inner retina, indicating diminished retinal iron levels with DFP treatment. Plastic sections showed that photoreceptor and RPE cells were well preserved in Hepc KO mice treated with DFP. Consistent with photoreceptor protection, the mRNA level of rhodopsin was significantly higher in retinas treated with DFP. The mRNA levels of oxidative stress–related genes heme oxygenase-1 and catalase were significantly lower in DFP-treated Hepc KO retinas. Finally, ERG rod a- and b- and cone b-wave amplitudes were significantly higher in DFP-treated mice.
Conclusions.
Long-term treatment with the oral iron chelator DFP diminished retinal and RPE iron levels and oxidative stress, providing significant protection against retinal degeneration caused by chronic systemic iron overload in Hepc KO mice. This indicates that iron chelation could be a long-term preventive treatment for retinal disease involving iron overload and oxidative stress.
Iron chelation provides a long-term preventive treatment for retinal disease involving iron overload and oxidative stress.
doi:10.1167/iovs.14-14568
PMCID: PMC4106252  PMID: 24970260
deferiprone; oxidative stress; hepcidin; retinal degeneration
6.  Hypoxia-Inducible Factor-2α Mediates the Adaptive Increase of Intestinal Ferroportin During Iron Deficiency in Mice 
Gastroenterology  2011;140(7):2044-2055.
Background & Aims
Iron deficiency and iron overload affect over a billion people, worldwide. Dietary iron absorption in the small intestine is required for systemic iron homeostasis. Ferroportin (FPN) is the only characterized, mammalian, basolateral iron exporter. Despite the importance of FPN in maintaining iron homeostasis, its in vivo mechanisms of regulation are unclear.
Methods
Systemic iron homeostasis was assessed in mice with intestine-specific disruption of genes encoding the von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (HIF)-1α, HIF-2α, and aryl hydrocarbon nuclear translocator (ARNT).
Results
We observed biphasic regulation of Fpn during iron deficiency. Fpn was rapidly induced under conditions of low iron, which required the transcription factor HIF-2α. Targeted disruption of HIF-2α in the intestine inhibited Fpn induction in mice with low iron, through loss of transcriptional activation. Analysis of the Fpn promoter and in vivo chromatin immunoprecipitation assays demonstrated that HIF-2α directly binds to the Fpn promoter and induces its expression, indicating a mechanism of transcriptional regulation of Fpn following changes in systemic levels of iron. During chronic iron deficiency, FPN protein levels also increased, via increased stability through a HIF-2α-independent pathway.
Conclusion
In mice, expression of the gene that encodes Fpn and its protein levels are regulated by distinct pathways to provide a rapid and sustained response to acute and chronic iron deficiency. Therapies that target FPN might be developed for patients with iron-related disorders..
doi:10.1053/j.gastro.2011.03.007
PMCID: PMC3109109  PMID: 21419768
ChIP assay; Hepcidin; diet; metabolism
7.  Absorption of Manganese and Iron in a Mouse Model of Hemochromatosis 
PLoS ONE  2013;8(5):e64944.
Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal iron absorption, is commonly caused by loss of HFE gene function. Both iron and manganese absorption are regulated by iron status, but the relationships between the transport pathways of these metals and how they are affected by HFE-associated hemochromatosis remain poorly understood. Loss of HFE function is known to alter the intestinal expression of DMT1 (divalent metal transporter-1) and Fpn (ferroportin), transporters that have been implicated in absorption of both iron and manganese. Although the influence of HFE deficiency on dietary iron absorption has been characterized, potential effects on manganese metabolism have yet to be explored. To investigate the role of HFE in manganese absorption, we characterized the uptake and distribution of the metal in Hfe−/− knockout mice after intravenous, intragastric, and intranasal administration of 54Mn. These values were compared to intravenous and intragastric administration of 59Fe. Intestinal absorption of 59Fe was increased and clearance of injected 59Fe was also increased in Hfe−/− mice compared to controls. Hfe−/− mice displayed greater intestinal absorption of 54Mn compared to wild-type Hfe+/+ control mice. After intravenous injection, the distribution of 59Fe to heart and liver was greater in Hfe−/− mice but no remarkable differences were observed for 54Mn. Although olfactory absorption of 54Mn into blood was unchanged in Hfe−/− mice, higher levels of intranasally-instilled 54Mn were associated with Hfe−/− brain compared to controls. These results show that manganese transport and metabolism can be modified by HFE deficiency.
doi:10.1371/journal.pone.0064944
PMCID: PMC3660331  PMID: 23705020
8.  Duodenal mRNA expression of iron related genes in response to iron loading and iron deficiency in four strains of mice 
Gut  2002;51(5):648-653.
Background: Although much progress has been made recently in characterising the proteins involved in duodenal iron trafficking, regulation of intestinal iron transport remains poorly understood. It is not known whether the level of mRNA expression of these recently described molecules is genetically regulated. This is of particular interest however as genetic factors are likely to determine differences in iron status among mouse strains and probably also contribute to the phenotypic variability seen with disruption of the haemochromatosis gene.
Aims: To investigate this issue, we examined concomitant variations in duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), hephaestin, stimulator of Fe transport (SFT), HFE, and transferrin receptor 1 (TfR1) transcripts in response to different dietary iron contents in the four mouse strains C57BL/6, DBA/2, CBA, and 129/Sv.
Subjects: Six mice of each strain were fed normal levels of dietary iron, six were subjected to the same diet supplemented with 2% carbonyl iron, and six were fed an iron deficient diet.
Methods: Quantification of mRNAs isolated from the duodenum was performed using real time reverse transcription-polymerase chain reaction.
Results: There was a significant increase in mRNA expression of Dcytb, DMT1, FPN1, and TfR1 when mice were fed an iron deficient diet, and a significant decrease in mRNA expression of these molecules when mice were fed an iron supplemented diet. Strain to strain differences were observed not only in serum transferrin saturations, with C57BL/6 mice having the lowest values, but also in hepatic iron stores and in duodenal mRNA expression of Dcytb, DMT1, FPN1, hephaestin, HFE, and TfR1.
Conclusions: The results favour some degree of genetic control of mRNA levels of these molecules.
PMCID: PMC1773425  PMID: 12377801
iron metabolism; duodenal iron absorption; dietary iron content; mRNA
9.  Progression, Symptoms and Psychosocial Concerns among Those Severely Affected by Multiple Sclerosis: A Mixed-Methods Cross-Sectional Study of Black Caribbean and White British People 
PLoS ONE  2013;8(10):e75431.
Objective
Multiple sclerosis is now more common among minority ethnic groups in the UK but little is known about their experiences, especially in advanced stages. We examine disease progression, symptoms and psychosocial concerns among Black Caribbean (BC) and White British (WB) people severely affected by MS.
Design
Mixed methods study of 43 BC and 43 WB people with MS (PwMS) with an Expanded Disability Status Scale (EDSS) ≥6 involving data from in clinical records, face-to-face structured interviews and a nested-qualitative component. Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) were calculated. To control for selection bias, propensity scores were derived for each patient and adjusted for in the comparative statistical analysis; qualitative data were analysed using the framework approach.
Results
Median EDSS for both groups was (6.5; range: 6.0–9.0). Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) based on neurological assessment of current EDSS scores identified BC PwMS were more likely to have aggressive disease (PI F = 4.04, p = 0.048, MSSS F = 10.30, p<0.001). Patients’ reports of the time required to reach levels of functional decline equivalent to different EDSS levels varied by group; EDSS 4: BC 2.7 years v/s WB 10.2 years (U = 258.50, p = 0.013), EDSS 6∶6.1 years BC v/s WB 12.7 years (U = 535.500, p = 0.011), EDSS 8: BC 8.7 years v/s WB 10.2 years. Both groups reported high symptom burden. BC PwMS were more cognitively impaired than WB PwMS (F = 9.65, p = 0.003). Thematic analysis of qualitative interviews provides correspondence with quantitative findings; more BC than WB PwMS referred to feelings of extreme frustration and unresolved loss/confusion associated with their rapidly advancing disease. The interviews also reveal the centrality, meanings and impact of common MS-related symptoms.
Conclusions
Delays in diagnosis should be avoided and more frequent reviews may be justified by healthcare services. Culturally acceptable interventions to better support people who perceive MS as an assault on identity should be developed to help them achieve normalisation and enhance self-identity.
doi:10.1371/journal.pone.0075431
PMCID: PMC3788806  PMID: 24098384
10.  Function of the hemochromatosis protein HFE: Lessons from animal models 
Hereditary hemochromatosis (HH) is caused by chronic hyperabsorption of dietary iron. Progressive accumulation of excess iron within tissue parenchymal cells may lead to severe organ damage. The most prevalent type of HH is linked to mutations in the HFE gene, encoding an atypical major histocompatibility complex classImolecule. Shortly after its discovery in 1996, the hemochromatosis protein HFE was shown to physically interact with transferrin receptor 1 (TfR1) and impair the uptake of transferrin-bound iron in cells. However, these findings provided no clue why HFE mutations associate with systemic iron overload. It was later established that all forms of HH result from misregulation of hepcidin expression. This liver-derived circulating peptide hormone controls iron efflux from duodenal enterocytes and reticuloendothelial macrophages by promoting the degradation of the iron exporter ferroportin. Recent studies with animal models of HH uncover a crucial role of HFE as a hepatocyte iron sensor and upstream regulator of hepcidin. Thus, hepatocyte HFE is indispensable for signaling to hepcidin, presumably as a constituent of a larger iron-sensing complex. A working model postulates that the signaling activity of HFE is silenced when the protein is bound to TfR1. An increase in the iron saturation of plasma transferrin leads to displacement of TfR1 from HFE and assembly of the putative iron-sensing complex. In this way, iron uptake by the hepatocyte is translated into upregulation of hepcidin, reinforcing the concept that the liver is the major regulatory site for systemic iron homeostasis, and not merely an iron storage depot.
doi:10.3748/wjg.14.6893
PMCID: PMC2773850  PMID: 19058322
Hepcidin; Iron metabolism; Transferrin; Hemojuvelin; Bone morphogenetic proteins
11.  Altered hepatic BMP signaling pathway in human HFE hemochromatosis 
Blood cells, molecules & diseases  2010;45(4):308-312.
Human hemochromatosis (HC) has been associated with the common C282Y polymorphism of HFE or rare pathogenic mutations of TfR2, HJV, FPN and HAMP. All forms of human HC seem to be caused by low or inadequate levels of hepcidin, the iron hormone. We and others have recently shown that Hfe−/−mice exhibit an impairment in the bone morphogenetic protein (BMP) signaling pathway controlling hepcidin. However, all data indicating the central role of BMPs in hepcidin regulation and an impaired BMP/SMAD signaling in HC have been collected in mice. In this study we investigated whether also in humans the expression of BMP signaling targets, SMAD7 and Id1, are associated with liver iron concentration (LIC) and whether such regulation is disrupted in HFE-HC. We correlated the mRNA expression, assessed by RT-PCR, of HAMP, SMAD7 and Id1 with LIC in liver biopsies from patients with normal iron status, HFE-HC or non-HC hepatic iron overload. We found that in human liver, not only HAMP, but also SMAD7 and Id1 mRNA significantly correlate with the extent of hepatic iron burden. However, this correlation is lost in patients with HFE-HC, but maintained in subjects with non-hemochromatotic iron overload. These data indicate that in human HFE-HC a disrupted BMP/SMAD signaling in the liver is key in the pathogenesis of the disease.
doi:10.1016/j.bcmd.2010.08.010
PMCID: PMC3295241  PMID: 20863724
iron overload; bone morphogenetic proteins; hepcidin; SMAD proteins
12.  Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1 
Background
Polymorphisms in the MHC class 1-like gene known as HFE have been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants of HFE are relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors.
Methods
We screened a panel of cytokines and trophic factors using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing different variants of HFE. The influence of cellular iron secretion on the potent chemokine monocyte chemoattractant protein-1 (MCP-1) was assessed using ferric ammonium citrate and the iron chelator, desferroxamine. Additionally, an antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their effects on MCP-1 secretion in the presence of HFE variants.
Results
Expression of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel of cytokines and trophic factors analyzed, only the release of MCP-1 was affected by the HFE variants. We further examined the relationship between iron and MCP-1 and found MCP-1 secretion tightly associated with intracellular iron status. A potential direct effect of HFE is considered because, despite having similar levels of intracellular iron, the association between HFE genotype and MCP-1 expression was different for the H63D and C282Y HFE variants. Moreover, HFE genotype was a factor in the effect of minocycline, a multifaceted antibiotic used in treating a number of neurologic conditions associated with inflammation, on MCP-1 secretion.
Conclusion
Our results demonstrate that HFE polymorphisms influence the synthesis and release of MCP-1. The mechanism of action involves cellular iron status but it appears there could be additional influences such as ER stress. Finally, these data demonstrate a pharmacogenetic effect of HFE polymorphisms on the ability of minocycline to inhibit MCP-1 secretion.
doi:10.1186/1742-2094-6-6
PMCID: PMC2656486  PMID: 19228389
13.  Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study 
PLoS Medicine  2013;10(6):e1001462.
In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease.
Please see later in the article for the Editors' Summary
Background
Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.
Methods and Findings
We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron.
Conclusions
Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Parkinson disease is a degenerative disorder of the central nervous system caused by the death of dopamine-generating cells in the substania nigra, a region of the midbrain. The earliest symptoms are usually movement-related and include tremor, slow movements, and difficulty walking, and later cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Parkinson disease affects around ten million people world-wide and incidence increases with age, with men more affected than women. To date, the causes of Parkinson disease remain unknown although a combination of genetic and environmental factors is thought to play a role. Identifying possible modifiable risks is an important step in the possible prevention of Parkinson disease.
Why Was This Study Done?
Previous studies have shown a possible association between lower blood levels of iron in people with Parkinson disease compared with controls, although the quality of these studies makes this finding difficult to interpret. So in this study, the researchers used a mendelian randomization approach to investigate whether there was any evidence of an effect of blood iron levels on the risk of Parkinson disease and if so to further explore the direction and scale of any link. Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in situations where it is inappropriate to perform a randomized controlled trial.
What Did the Researchers Do and Find?
The researchers estimated the effect of blood iron levels on the risk of Parkinson disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson disease, which included a total of 20,809 people with Parkinson disease and 88,892 controls from Europe and North America. They then performed three separate mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson disease per 10 µg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined mendelian randomization estimate reflects an effect of iron over the course of a lifetime.
What Do These Findings Mean?
These findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson disease, although the underlying mechanism remains unclear. Furthermore, although mendelian randomization is an increasingly used approach to address the issue of classical confounding, there may be remaining confounding factors specific of mendelian randomization that may influence the interpretation of this study. Nevertheless, the results of this analysis have potentially important implications for future research into the prevention of Parkinson disease. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001462.
The National Institutes of Neurological Disorder and Stroke, MedlinePlus, and NHS Choices have several pages with comprehensive information on Parkinson disease
Wikipedia gives an explanation of mendelian randomization (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001462
PMCID: PMC3672214  PMID: 23750121
14.  Heterozygous β‐globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis C 
Gut  2006;56(5):693-698.
Background
Iron accumulation is a well‐known risk factor for the progression of chronic hepatitis C (CHC) to fibrosis. However, the profibrogenic role of the genes controlling iron homeostasis is still controversial.
Aim
To evaluate the relative role of haemachromatosis (HFE), ferroportin and β‐globin gene mutations in promoting iron accumulation and fibrosis in patients with CHC.
Methods
Genetic analysis was performed together with the assessment of hepatic iron content and histology in 100 consecutive HIV‐antibody and hepatitis B surface antigen‐negative patients with biopsy‐proven CHC.
Results
Among the patients investigated, 12 were heterozygous for various β‐globin gene mutations (39[C→T], IVS1.1[G→A], 22 7 bp deletion and IVS1.6[T→C]) and 29 carried HFE (C282Y, H63D and S65C) gene mutations. One further patient was heterozygous for both HFE (H63D) and β‐globin (39[C→T]) variants, whereas 58 had the wild‐type alleles of both the genes. Hepatic iron concentration (HIC) and hepatic stainable iron were significantly higher (p<0.05) in patients with CHC carrying β‐globin mutations than in those with HFE mutations or the wild‐type alleles. Multivariate analysis confirmed that the presence of β‐globin mutations was independently associated with both HIC (p = 0.008) and hepatic‐stainable iron (odds ratio (OR) 6.11; 95% CI 1.56 to 23.92; p = 0.009). Moderate/severe fibrosis or cirrhosis (Ishak's score >2) was observed in 48 of 100 patients. Logistic regression demonstrated that age (OR 1.05; 95% CI 1.02 to 1.09; p<0.005) and β‐globin mutations (OR 4.99; 95% CI 1.22 to 20.3; p = 0.025) were independent predictors of the severity of fibrosis.
Conclusions
Heterozygosis for β‐globin mutations is a novel risk factor for both hepatic iron accumulation and the progression to fibrosis in patients with CHC.
doi:10.1136/gut.2006.106641
PMCID: PMC1942129  PMID: 17135308
15.  Prevalence of H63D, S65C and C282Y hereditary hemochromatosis gene mutations in Slovenian population by an improved high-throughput genotyping assay 
BMC Medical Genetics  2007;8:69.
Background
Hereditary hemochromatosis (HH) is a common genetic disease characterized by excessive iron overload that leads to multi-organ failure. Although the most prevalent genotype in HH is homozygosity for C282Y mutation of the HFE gene, two additional mutations, H63D and S65C, appear to be associated with a milder form of HH. The aim of this study was to develop a high-throughput assay for HFE mutations screening based on TaqMan technology and to determine the frequencies of HFE mutations in the Slovenian population.
Methods
Altogether, 1282 randomly selected blood donors from different Slovenian regions and 21 HH patients were analyzed for the presence of HFE mutations by an in-house developed real-time PCR assay based on TaqMan technology using shorter non-interfering fluorescent single nucleotide polymorphism (SNP)-specific MGB probes. The assay was validated by RFLP analysis and DNA sequencing.
Results
The genotyping assay of the H63D, S65C and C282Y mutations in the HFE gene, based on TaqMan technology proved to be fast, reliable, with a high-throughput capability and 100% concordant with genotypes obtained by RFLP and DNA sequencing. The observed frequency of C282Y homozygotes in the group of HH patients was only 48%, others were of the heterogeneous HFE genotype. Among 1282 blood donors tested, the observed H63D, S65C and C282Y allele frequency were 12.8% (95% confidence interval (CI) 11.5 – 14.2%), 1.8% (95% CI 1.4 – 2.5%) and 3.6% (95% CI 3.0 – 4.5%), respectively. Approximately 33% of the tested subjects had at least one of the three HH mutations, and 1% of them were C282Y homozygotes or compound heterozygotes C282Y/H63D or C282Y/S65C, presenting an increased risk for iron overload disease. A significant variation in H63D allele frequency was observed for one of the Slovenian regions.
Conclusion
The improved real-time PCR assay for H63D, S65C and C282Y mutations detection is accurate, fast, cost-efficient and ready for routine screening and diagnostic procedures. The genotype frequencies in the Slovenian population agree with those reported for the Central European populations although some deviations where observed in comparison with other populations of Slavic origin. Regional distribution of the mutations should be considered when planning population screening.
doi:10.1186/1471-2350-8-69
PMCID: PMC2253505  PMID: 18036208
16.  Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection 
NOS2-derived nitric oxide drives ferroportin-1–mediated iron export in Salmonella-infected macrophages, thus limiting bacterial growth.
Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2−/− macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2−/− macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2−/− macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages
doi:10.1084/jem.20121946
PMCID: PMC3646493  PMID: 23630227
17.  Silencing airway epithelial cell-derived hepcidin exacerbates sepsis-induced acute lung injury 
Critical Care  2014;18(4):470.
Introduction
The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infections and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury.
Methods
Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the seven-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated.
Results
The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice.
Conclusions
Airway epithelial cell-derived hepcidin plays an important role in CLP-induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages.
doi:10.1186/s13054-014-0470-8
PMCID: PMC4243715  PMID: 25096529
18.  Allele frequencies of hemojuvelin gene (HJV) I222N and G320V missense mutations in white and African American subjects from the general Alabama population 
BMC Medical Genetics  2004;5:29.
Background
Homozygosity or compound heterozygosity for coding region mutations of the hemojuvelin gene (HJV) in whites is a cause of early age-of-onset iron overload (juvenile hemochromatosis), and of hemochromatosis phenotypes in some young or middle-aged adults. HJV coding region mutations have also been identified recently in African American primary iron overload and control subjects. Primary iron overload unexplained by typical hemochromatosis-associated HFE genotypes is common in white and black adults in Alabama, and HJV I222N and G320V were detected in a white Alabama juvenile hemochromatosis index patient. Thus, we estimated the frequency of the HJV missense mutations I222N and G320V in adult whites and African Americans from Alabama general population convenience samples.
Methods
We evaluated the genomic DNA of 241 Alabama white and 124 African American adults who reported no history of hemochromatosis or iron overload to detect HJV missense mutations I222N and G320V using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Analysis for HJV I222N was performed in 240 whites and 124 African Americans. Analysis for HJV G320V was performed in 241 whites and 118 African Americans.
Results
One of 240 white control subjects was heterozygous for HJV I222N; she was also heterozygous for HFE C282Y, but had normal serum iron measures and bone marrow iron stores. HJV I222N was not detected in 124 African American subjects. HJV G320V was not detected in 241 white or 118 African American subjects.
Conclusions
HJV I222N and G320V are probably uncommon causes or modifiers of primary iron overload in adult whites and African Americans in Alabama. Double heterozygosity for HJV I222N and HFE C282Y may not promote increased iron absorption.
doi:10.1186/1471-2350-5-29
PMCID: PMC544351  PMID: 15610558
19.  Kinetics of iron removal by phlebotomy in patients with iron overload after allogeneic hematopoietic cell transplantation 
Excess body iron could persist for years after allogeneic hematopoietic cell transplantation (HCT) with possible deleterious sequels. An iron depletive therapy with phlebotomy seems rational. Kinetics of iron removal by phlebotomy without erythropoietin support in non-thalassemic adult patients with iron overload after HCT and the impact of pre- and post-HCT hemochromatosis (HFE) genotype on iron mobilization were investigated. Patients and methods: Phlebotomy was initiated in 61 recipients of allografts due to hematologic malignancies (median age 48 years) after a median of 18 months. The prephlebotomy median serum ferritin (SF) was 1697ng/ml and the median number of blood transfusions 28 units. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphates (AP), and bilirubin were elevated in 55.7%, 64% and 11.5% patients respectively. HFE-genotype was elucidated by polymerase chain reaction using hybridization probes and melting curve analysis. Results: Phlebotomy was well-tolerated irrespective of age or conditioning. A negative iron balance in 80% of patients (median SF 1086 ng/ml) and a rise in hemoglobin were observed (p<0.0001). Higher transfusional burden and SF were associated with a greater iron mobilization per session (p=0.02). In 58% of patients, a plateau after an initial steady decline in SF was followed by a second decline under further phlebotomy. The improvement in ALT (p=0.002), AST (p=0.03), AP (p=0.01), and bilirubin (p<0.0001) did not correlate with the decline in SF. Mutant HFE-gene variants were detected in 14/55 (25%) pre-HCT and 22/55 (40%) patients post-HCT. Overall, dissimilar pre- and posttransplantational HFE-genotypes were detected in 20/55 (40%) patients. Posttransplantational mutant HFE variants correlated with a slower decline in SF (p=0.007). Conclusions: Phlebotomy is a convenient therapy of iron overload in survivors of HCT. A negative iron balance and a rise in hemoglobin were observed in the majority of patients. Liver dysfunction improved irrespective of SF reduction suggesting a probable rapid decline of the deleterious labile plasma iron. In recipients of grafts with mutant HFE variants a “mixed chimerism” of HFE in body tissues might be created with a change in the set point for iron regulation. The transient plateau in SF after an initial decline might reflect iron mobilization from various tissues.
PMCID: PMC3512175  PMID: 23226624
Iron overload; ferritin; phlebotomy; allogeneic HCT
20.  Role of duodenal iron transporters and hepcidin in patients with alcoholic liver disease 
Patients with alcoholic liver disease (ALD) often display disturbed iron indices. Hepcidin, a key regulator of iron metabolism, has been shown to be down-regulated by alcohol in cell lines and animal models. This down-regulation led to increased duodenal iron transport and absorption in animals. In this study, we investigated gene expression of duodenal iron transport molecules and hepcidin in three groups of patients with ALD (with anaemia, with iron overload and without iron overload) and controls. Expression of DMT1, FPN1, DCYTB, HEPH, HFE and TFR1 was measured in duodenal biopsies by using real-time PCR and Western blot. Serum hepcidin levels were measured by using ELISA. Serum hepcidin was decreased in patients with ALD. At the mRNA level, expressions of DMT1, FPN1 and TFR1 genes were significantly increased in ALD. This pattern was even more pronounced in the subgroups of patients without iron overload and with anaemia. Protein expression of FPN1 paralleled the increase at the mRNA level in the group of patients with ALD. Serum ferritin was negatively correlated with DMT1 mRNA. The down-regulation of hepcidin expression leading to up-regulation of iron transporters expression in the duodenum seems to explain iron metabolism disturbances in ALD. Alcohol consumption very probably causes suppression of hepcidin expression in patients with ALD.
doi:10.1111/jcmm.12310
PMCID: PMC4196659  PMID: 24894955
DMT1; FPN1; DCYTB; HEPH; TFR1; HFE; hepcidin; alcoholic liver disease; iron; gene expression
21.  Effects of various metal ions on the gene expression of iron exporter ferroportin-1 in J774 macrophages 
Nutrition Research and Practice  2008;2(4):317-321.
Macrophages play a key role in iron metabolism by recycling iron through erythrophagocytosis. Ferroportin-1 (FPN1) is a transporter protein that is known to mediate iron export from macrophages. Since divalent metals often interact with iron metabolism, we examined if divalent metals could regulate the expression of FPN1 in macrophages. J774 macrophage cells were treated with copper, manganese, zinc, or cobalt at 10, 50, or 100 µM for 16 to 24 h. Then, FPN1 mRNA and protein levels were determined by quantitative real-time PCR and Western blot analyses, respectively. In addition, effects of divalent metals on FPN1 promoter activity were examined by luciferase reporter assays. Results showed that copper significantly increased FPN1 mRNA levels in a dose-dependent manner. The copper-induced expression of FPN1 mRNA was associated with a corresponding increase in FPN1 protein levels. Also, copper directly stimulated the activity of FPN1 promoter-driven reporter construct. In contrast, manganese and zinc had no effect on the FPN1 gene expression in J774 cells. Interestingly, cobalt treatment in J774 cells decreased FPN1 protein levels without affecting FPN1 mRNA levels. In conclusion, our study results demonstrate that divalent metals differentially regulate FPN1 expression in macrophages and indicate a potential interaction of divalent metals with the FPN1-mediated iron export in macrophages.
doi:10.4162/nrp.2008.2.4.317
PMCID: PMC2788185  PMID: 20016736
Ferroportin-1; divalent metals; copper; macrophages; iron export
22.  Clinical, Pathological, and Molecular Correlates in Ferroportin Disease. A Study Of Two Novel Mutations 
Journal of hepatology  2008;49(4):664-671.
Background/Aims
Clinico-pathological manifestations of Ferroportin (Fpn) Disease (FD) are heterogeneous, with some patients presenting with iron overload predominantly in macrophages (“M” phenotype), others predominantly in hepatocytes (“H” phenotype). This appears to reflect functional heterogeneity of Fpn mutants, with loss-of-function generally resulting in the M type.
Methods
Two unrelated probands with “non-HFE” hemochromatosis were screened for Fpn mutations. Mutants were functionally characterized by immunofluorescence microscopy, evaluation of their ability to bind hepcidin and export iron, and by expressing them in zebrafish.
Results
Two novel Fpn mutations were identified: I152F in patient-1, presenting with typical M phenotype; and L233P in patient-2, presenting with ambiguous features (massive overload in both macrophages and hepatocytes). Molecular studies suggested loss of function in both cases. The I152F, normally localized on cell membrane and internalized by hepcidin, showed a unique “primary” deficit of iron export capability. The L233P did not appropriately traffic to cell surface. Loss of function was confirmed by expressing both mutants in vivo in zebrafish, resulting in iron limited erythropoiesis. Clinical manifestations were likely enhanced in both patients by nongenetic factors (HCV, alcohol).
Conclusions
The combination of careful review of clinico-pathological data with molecular studies can yield compelling explanations for phenotype heterogeneity in FD.
doi:10.1016/j.jhep.2008.05.028
PMCID: PMC2605969  PMID: 18713659
iron overload; ferroportin; hemochromatosis; hepcidin; zebrafish
23.  Genome-Wide Association Study Identifies Genetic Loci Associated with Iron Deficiency 
PLoS ONE  2011;6(3):e17390.
The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10−7 for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P = 7.0×10−9, corrected P = 0.012) was replicated within the VA samples (observed P = 0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.
doi:10.1371/journal.pone.0017390
PMCID: PMC3069025  PMID: 21483845
24.  Ferroportin disease: A systematic meta-analysis of clinical and molecular findings☆ 
Journal of Hepatology  2010;53(5-3):941-949.
Background & Aims
Classical ferroportin disease is characterized by hyperferritinemia, normal transferrin saturation, and iron overload in macrophages. A non-classical form is characterized by additional hepatocellular iron deposits and a high transferrin saturation. Both forms demonstrate autosomal dominant transmission and are associated with ferroportin gene (SLC40A1) mutations. SLC40A1 encodes a cellular iron exporter expressed in macrophages, enterocytes, and hepatocytes. The aim of the analysis is to determine the penetrance of SLC40A1 mutations and to evaluate in silico tools to predict the functional impairment of ferroportin mutations as an alternative to in vitro studies.
Methods
We conducted a systematic review of the literature and meta-analysis of the biochemical presentation, genetics, and pathology of ferroportin disease.
Results
Of the 176 individuals reported with SLC40A1 mutations, 80 were classified as classical phenotype with hyperferritinemia and normal transferrin saturation. The non-classical phenotype with hyperferritinemia and elevated transferrin saturation was present in 53 patients. The remaining patients had normal serum ferritin or the data were reported incompletely. Despite an increased hepatic iron concentration in all biopsied patients, significant fibrosis or cirrhosis was present in only 11%. Hyperferritinemia was present in 86% of individuals with ferroportin mutations. Bio-informatic analysis of ferroportin mutations showed that the PolyPhen score has a sensitivity of 99% and a specificity of 67% for the discrimination between ferroportin mutations and polymorphisms.
Conclusions
In contrast to HFE hemochromatosis, ferroportin disease has a high penetrance, is genetically heterogeneous and is rarely associated with fibrosis. Non-classical ferroportin disease is associated with a higher risk of fibrosis and a more severe overload of hepatic iron.
doi:10.1016/j.jhep.2010.05.016
PMCID: PMC2956830  PMID: 20691492
AUROC, area under the receiver operator curve; ER, endoplasmic reticulum; HIC, hepatic iron concentration; JAK2, Janus Kinase 2; MRI, magnetic resonance imaging; PolyPhen, polymorphism phenotyping; ROC, receiver operator curve; SIFT, sorting intolerant from tolerant; SLC40A1; Hemochromatosis type IV; Iron; Bio-informatics; SLC11A3; IREG1; FPN1; PolyPhen
25.  Brain and retinal ferroportin 1 dysregulation in polycythaemia mice 
Brain research  2009;1289:85-95.
Disruption of iron homeostatsis within the central nervous system (CNS) can lead to profound abnormalities during both development and aging in mammals. The radiation-induced polycythaemia (Pcm) mutation, a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), disrupts transcriptional and post-transcriptional regulation of this pivotal iron transporter. This regulatory mutation induces dynamic alterations in peripheral iron homeostatis such that newborn homozygous Pcm mice exhibit iron deficiency anemia with increased duodenal Fpn1 expression while adult homozygotes display decreased Fpn1 expression and anemia despite organismal iron overload. Herein we report the impact of the Pcm microdeletion on iron homeostasis in two compartments of the the central nervous system: brain and retina. At birth, Pcm homozygotes show a marked decrease in brain iron content and reduced levels of Fpn1 expression. Upregulation of transferrin receptor 1 (TfR1) in brain microvasculature appears to mediate the compensatory iron uptake during postnatal development and iron content in Pcm brain is restored to wildtype levels by 7 weeks of age. Similarly, changes in expression are transient and expression of Fpn1 and TfR1 is indistinguishable between Pcm homozygotes and wildtype by 12 weeks of age. Strikingly, the adult Pcm brain is effectively protected from the peripheral iron overload and maintains normal iron content. In contrast to Fpn1 downregulation in perinatal brain, the retina of Pcm homozygotes reveals increased levels of Fpn1 expression. While retinal morphology appears normal at birth and during early postnatal development, adult Pcm mice demonstrate a marked, age-dependent loss of photoreceptors. This phenotype demonstrates the importance of iron homeostasis in retinal health.
doi:10.1016/j.brainres.2009.06.098
PMCID: PMC2736625  PMID: 19596281
Polycythaemia; Ferroportin; Brain; Retina; Iron

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