|
1
|
Suh SH, Oh TR, Choi HS, Kim CS, Bae EH, Ma SK, Oh KH, Lee KB, Jung JY, Kim SW, on behalf of the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) Investigators. Predictive Value of Serum Hepcidin Levels for the Risk of Incident End-Stage Kidney Disease in Patients with Chronic Kidney Disease: The KNOW-CKD. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:492-503. [PMID: 39664339 PMCID: PMC11631166 DOI: 10.1159/000542057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 10/14/2024] [Indexed: 12/13/2024]
Abstract
Introduction Despite the pivotal role of hepcidin in the development of anemia among the patients with chronic kidney disease (CKD), the association between serum hepcidin levels and CKD progression has been never investigated. We here hypothesized that elevation in serum hepcidin levels might be associated with the risk of incident end-stage kidney disease (ESKD) among the patients with pre-dialysis CKD. Methods A total of 2,109 patients with pre-dialysis CKD at stages 1 to pre-dialysis 5 were categorized into the quartiles by serum hepcidin levels. The study outcome was incident ESKD. The median duration of follow-up was 7.9 years. Results The analysis of the baseline characteristics revealed that unfavorable clinical features were in general associated with higher serum hepcidin levels. The cumulative incidence of ESKD was significantly differed by serum hepcidin levels, with the highest incidence in the 4th quartile (p < 0.001, by log-rank test). Cox regression analysis demonstrated that, compared to the 1st quartile, the risk of incident ESKD is significantly increased in the 4th quartile (adjusted hazard ratio 1.372, 95% confidence interval 1.070-1.759). Penalized spline curve analysis illustrated a linear, positive correlation between serum hepcidin levels and the risk of incident ESKD. Subgroup analyses revealed that the association is significantly more prominent in the patients with advanced CKD (i.e., estimated glomerular filtration rate <45 mL/min/1.73 m2). Conclusion Elevation in serum hepcidin levels is significantly associated with the risk of incident ESKD among the patients with pre-dialysis CKD.
Collapse
Affiliation(s)
- Sang Heon Suh
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Tae Ryom Oh
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Hong Sang Choi
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Chang Seong Kim
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyu-Beck Lee
- Division of Nephrology, Department of Internal Medicine, Kangbuk Samsung Hospital, Seoul, Republic of Korea
| | - Ji Yong Jung
- Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
| | - on behalf of the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) Investigators
- Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hospital, Gwangju, Republic of Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Division of Nephrology, Department of Internal Medicine, Kangbuk Samsung Hospital, Seoul, Republic of Korea
- Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea
| |
Collapse
|
|
2
|
A Novel Hepcidin Mutation. Transfus Clin Biol 2023:S1246-7820(23)00037-X. [PMID: 36925058 DOI: 10.1016/j.tracli.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/02/2023] [Accepted: 03/02/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND The bioactive peptide hormone hepcidin-25 regulates iron levels by inhibiting iron transport to plasma via ferroportin. Hepcidin-25 is synthesized in the liver where the 84 amino acids pro-hepcidin is cleaved into the bioactive hepcidin-25. A patient admitted to the hospital presented with infertility and fatigue. METHODS Genomic DNA was purified from whole blood using the Maxwell 16 system (Promega). MLPA analysis was performed to detect large genomic rearrangements using the SALSA MLPA kit # P347, Hemochromatosis (MRC Holland, Holland). Plasma hepcidin measurements were performed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). RESULTS A novel HAMP mutation (homozygous one base deletion in c.215delG, p.Cys72Serfs*?) was detected. The deletion in nucleotide 215 causes a frameshift altering the predicted protein sequence from cysteine13 in mature peptide. Whether this leads to nonsense mediated decay of the mRNA or synthesis of an aberrant peptide in unknown, but bioactive hepcidin-25 was undetectable in plasma. The patient had massive iron overload with ferritin up to 8360 µg/L. He was anaemic with a Hb at 7.0 mmol/L (11.3 g/dL) and suffered from hypogonadotropic hypogonadism with a total testosterone of 1.2 nmol/l . Continued treatment with venesection and gonadotropins led to reduced fatigue, reduction in iron overload, a normalized Hb and improvement of semen quality. CONCLUSION A novel hepcidin mutation was detected in a patient with massive iron overload, fatigue and hypogonadotropic hypogonadism.
Collapse
|
|
3
|
Kowdley DS, Kowdley KV. Appropriate Clinical Genetic Testing of Hemochromatosis Type 2-4, Including Ferroportin Disease. Appl Clin Genet 2021; 14:353-361. [PMID: 34413666 PMCID: PMC8369226 DOI: 10.2147/tacg.s269622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/18/2021] [Indexed: 11/23/2022] Open
Abstract
Hereditary hemochromatosis (HH) is an inherited iron overload disorder due to a deficiency of hepcidin, or a failure of hepcidin to degrade ferroportin. The most common form of HH, Type 1 HH, is most commonly due to a homozygous C282Y mutation in HFE and is relatively well understood in significance and action; however, other rare forms of HH (Types 2–4) exist and are more difficult to identify and diagnose in clinical practice. In this review, we describe the clinical characteristics of HH Type 2–4 and the mutation patterns that have been described in these conditions. We also review the different methods for genetic testing available in clinical practice and a pragmatic approach to the patient with suspected non-HFE HH.
Collapse
Affiliation(s)
- Devan S Kowdley
- Liver Institute Northwest and Elson S. Floyd College of Medicine, Washington State University, Seattle, WA, USA
| | - Kris V Kowdley
- Liver Institute Northwest and Elson S. Floyd College of Medicine, Washington State University, Seattle, WA, USA
| |
Collapse
|
|
4
|
Kang W, Barad A, Clark AG, Wang Y, Lin X, Gu Z, O'Brien KO. Ethnic Differences in Iron Status. Adv Nutr 2021; 12:1838-1853. [PMID: 34009254 PMCID: PMC8483971 DOI: 10.1093/advances/nmab035] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023] Open
Abstract
Iron is unique among all minerals in that humans have no regulatable excretory pathway to eliminate excess iron after it is absorbed. Iron deficiency anemia occurs when absorbed iron is not sufficient to meet body iron demands, whereas iron overload and subsequent deposition of iron in key organs occur when absorbed iron exceeds body iron demands. Over time, iron accumulation in the body can increase risk of chronic diseases, including cirrhosis, diabetes, and heart failure. To date, only ∼30% of the interindividual variability in iron absorption can be captured by iron status biomarkers or iron regulatory hormones. Much of the regulation of iron absorption may be under genetic control, but these pathways have yet to be fully elucidated. Genome-wide and candidate gene association studies have identified several genetic variants that are associated with variations in iron status, but the majority of these data were generated in European populations. The purpose of this review is to summarize genetic variants that have been associated with alterations in iron status and to highlight the influence of ethnicity on the risk of iron deficiency or overload. Using extant data in the literature, linear mixed-effects models were constructed to explore ethnic differences in iron status biomarkers. This approach found that East Asians had significantly higher concentrations of iron status indicators (serum ferritin, transferrin saturation, and hemoglobin) than Europeans, African Americans, or South Asians. African Americans exhibited significantly lower hemoglobin concentrations compared with other ethnic groups. Further studies of the genetic basis for ethnic differences in iron metabolism and on how it affects disease susceptibility among different ethnic groups are needed to inform population-specific recommendations and personalized nutrition interventions for iron-related disorders.
Collapse
Affiliation(s)
- Wanhui Kang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Alexa Barad
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Andrew G Clark
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA,Department of Computational Biology, Cornell University, Ithaca, NY, USA
| | - Yiqin Wang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Xu Lin
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zhenglong Gu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | | |
Collapse
|
|
5
|
Dixit SP, Rajan L, Palaniswamy D, Mohankumar SK. Importance of Iron Absorption in Human Health: An Overview. CURRENT NUTRITION & FOOD SCIENCE 2021. [DOI: 10.2174/1573401316999200801021752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Iron is one of the essential elements required for human health, as it plays a vital role in
a number of metabolic, growth, and developmental processes, including erythropoiesis, DNA synthesis,
electron transport, and others. Iron deficiency is a concern in both developing and developed
(industrialized) countries, and, in particular, young women are highly vulnerable. This review investigates
the dietary and genetic determinants of iron metabolism in the human body and a possible
solution to combat iron deficiency by exploring various targets. Hence, this review mainly focuses
on the assessment of dietary and genetic factors affecting the iron bioavailability and homeostasis
and collates the available information from 2000 to till date from the Pubmed database. The dietary
factors, including ascorbic acid, an important factor in animal protein foods (meat, fish, and
poultry), enhance iron absorption whereas the phytic acid, soy protein, calcium, and polyphenols
have been reported to inhibit iron absorption. However, the effects of these dietary factors on iron
absorption do not necessarily translate into an association with iron status and iron stores (serum
ferritin concentration). Moreover, the genetic factors influence the absorption of iron involving
HFE, TFR2, FPN1, and HAMP in humans. Further research is needed to determine optimal dietary
recommendations for both the prevention and treatment of iron deficiency.
Collapse
Affiliation(s)
- Satya P. Dixit
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rockland’s, Ooty 643001, Tamil Nadu, India
| | - Logesh Rajan
- TIFAC CORE in Herbal Drugs, Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rockland’s, Ooty 643001, Tamil Nadu, India
| | - Dhanabal Palaniswamy
- TIFAC CORE in Herbal Drugs, Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rockland’s, Ooty 643001, Tamil Nadu, India
| | - Suresh K. Mohankumar
- TIFAC CORE in Herbal Drugs, Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rockland’s, Ooty 643001, Tamil Nadu, India
| |
Collapse
|
|
6
|
Pandey S, Pandey SK, Shah V. Role of HAMP Genetic Variants on Pathophysiology of Iron Deficiency Anemia. Indian J Clin Biochem 2018; 33:479-482. [PMID: 30319197 DOI: 10.1007/s12291-017-0707-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 10/16/2017] [Indexed: 12/21/2022]
Abstract
Hepcidin is a 25-amino acid peptide hormone produced by hepatocytes and plays a key role in body iron metabolism. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemia, and its excess is associated with anemia of inflammation, chronic disease and iron deficiency anemia (IDA). The aims of this study was to evaluate HAMP gene mutation, namely IVS2 + 1(-G) (c.148-150 + 1del) and Gly71 Asp (c.212G > A (rs104894696) association with iron status in IDA conditions. Our study participants were 500 IDA patients and 550 age and sex-matched healthy controls. Hepcidin, ferritin and CRP analysis was done by ELISA method while ESR analysis was done according to Wintrobe method. CBC analysis was done by auto-analyzer. Two mutations in the HAMP genes were analysed by PCR RFLP method. Among the IDA patients, 7 were heterozygous for Met50del IVS2 + 1(-G) mutation. Nine IDA patients were heterozygous for G71D G-A mutation and homozygous were not identified in both mutations.Controls were showing heterozygous frequency 1.8 and 2.1% of Met50del IVS2 + 1(-G) and G71D G-A mutations respectively. Mutation of HAMP (Met50del IVS2 + 1(-G) and G71D G-A) were clinically associated with IDA and act as modulator of disease.
Collapse
Affiliation(s)
- S Pandey
- Centre for Biotechnology Studies, Awadhesh Pratap Singh University, Rewa, M.P. 486003 India
| | - S K Pandey
- Centre for Biotechnology Studies, Awadhesh Pratap Singh University, Rewa, M.P. 486003 India
| | - V Shah
- Centre for Biotechnology Studies, Awadhesh Pratap Singh University, Rewa, M.P. 486003 India
| |
Collapse
|
|
7
|
The C19S Substitution Enhances the Stability of Hepcidin While Conserving Its Biological Activity. Protein J 2018; 37:113-121. [PMID: 29430595 DOI: 10.1007/s10930-018-9759-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Hepcidin, the key hormone of iron homeostasis is responsible for lowering the serum iron level through its interaction with iron exporter ferroportin. Thus, hepcidin agonists provide a promising opportunity in the treatment of iron disorders caused by lacking or decreased hepcidin expression. We investigated the importance of each of the eight highly conserved cysteines for the biological activity of hepcidin. Eight cysteine mutants were created with site directed mutagenesis. The binding ability of these hepcidin mutants to the hepcidin receptor ferroportin was determined using bacterial two-hybrid system and WRL68 human hepatic cells. The biological activity of hepcidin mutants was determined by western blot analysis of ferroportin internalization and ferroportin ubiquitination. To investigate the effect of mutant hepcidins on the iron metabolism of the WRL68 cells, total intracellular iron content was measured with a colorimetric assay. The stability of M6 hepcidin mutant was determined using ELISA technique. Our data revealed that serine substitution of the sixth cysteine (M6) yielded a biologically active but significantly more stable peptide than the original hormone. This result may provide a promising hepcidin agonist worth testing in animal models.
Collapse
|
|
8
|
Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease. Blood 2018; 132:101-110. [PMID: 29743178 DOI: 10.1182/blood-2018-02-830562] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/03/2018] [Indexed: 12/15/2022] Open
Abstract
The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV, HAMP, or TFR2 genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP, and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 patients with non-HFE HH was extracted from 53 publications and compared with data from 984 patients with HFE-p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy, which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH, and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in patients with HFE HH.
Collapse
|
|
9
|
Fonseca PFS, Cançado RD, Uellendahl Lopes MM, Correia E, Lescano MA, Santos PCJL. HAMP Gene Mutation Associated with Juvenile Hemochromatosis in Brazilian Patients. Acta Haematol 2016; 135:228-31. [PMID: 27007796 DOI: 10.1159/000444119] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 01/17/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Paula Fernanda Silva Fonseca
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sx00E3;o Paulo Medical School, Sx00E3;o Paulo, Brazil
| | | | | | | | | | | |
Collapse
|
|
10
|
Silva B, Pita L, Gomes S, Gonçalves J, Faustino P. The hepcidin gene promoter nc.-1010C > T; -582A > G haplotype modulates serum ferritin in individuals carrying the common H63D mutation in HFE gene. Ann Hematol 2015; 93:2063-6. [PMID: 25015054 DOI: 10.1007/s00277-014-2160-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 07/02/2014] [Indexed: 12/29/2022]
Abstract
Hereditary hemochromatosis is an autosomal recessive disorder characterized by severe iron overload. It is usually associated with homozygosity for the HFE gene mutation c.845G > A; p.C282Y. However, in some cases, another HFE mutation (c.187C > G; p.H63D) seems to be associated with the disease. Its penetrance is very low, suggesting the possibility of other iron genetic modulators being involved. In this work, we have screened for HAMP promoter polymorphisms in 409 individuals presenting normal or increased serum ferritin levels together with normal or H63D-mutated HFE genotypes. Our results show that the hepcidin gene promoter TG haplotype, originated by linkage of the nc.-1010C > T and nc.-582A > G polymorphisms, is more frequent in the HFE_H63D individuals presenting serum ferritin levels higher than 300 μg/L than in those presenting the HFE_H63D mutation but with normal serum ferritin levels or in the normal control group.Moreover, it was observed that the TG haplotype was associated to increased serum ferritin levels in the overall pool of HFE_H63D individuals. Thus, our data suggest that screening for these polymorphisms could be of interest in order to explain the phenotype. However, this genetic condition seems to have no clinical significance.
Collapse
|
|
11
|
Hattori A, Tomosugi N, Tatsumi Y, Suzuki A, Hayashi K, Katano Y, Inagaki Y, Ishikawa T, Hayashi H, Goto H, Wakusawa S. Identification of a novel mutation in the HAMP gene that causes non-detectable hepcidin molecules in a Japanese male patient with juvenile hemochromatosis. Blood Cells Mol Dis 2012; 48:179-82. [DOI: 10.1016/j.bcmd.2012.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Revised: 12/29/2011] [Accepted: 12/30/2011] [Indexed: 10/14/2022]
|
|
12
|
Abstract
Primary iron overload is one of the most common inherited diseases worldwide. Several genetic mutations underlie the various forms of the disease, which have similar pathophysiological profiles but distinct clinical presentations. Patients with hereditary hemochromatosis absorb too much iron from the diet, which accumulates over time within parenchymal cells. This accumulation leads to eventual organ failure as a consequence of iron-mediated formation of free radicals. The mechanism underlying this excessive absorption of iron is a sensing defect caused by the reduced formation of hepcidin, the master regulator of iron homeostasis, as a consequence of mutations in the genes encoding several membrane-bound signaling molecules present on hepatocytes. A considerable number of carriers of these specific genetic mutations, however, do not develop iron overload, indicating that additional genetic and environmental factors modify the severity and clinical penetrance of disease. In affected patients, early initiation of treatment by phlebotomy can prevent organ damage. Genetic screening of first-degree relatives can be also used to identify individuals at risk. Our expanding knowledge of the regulation of iron metabolism and the role of factors that modify the severity of the disease may lead to the design of new and improved treatments.
Collapse
|
|
13
|
Hepcidin in acute iron toxicity. Am J Emerg Med 2009; 27:761-4. [DOI: 10.1016/j.ajem.2008.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2008] [Revised: 05/29/2008] [Accepted: 06/02/2008] [Indexed: 01/08/2023] Open
|
|
14
|
Altès A, Bach V, Ruiz A, Esteve A, Felez J, Remacha AF, Sardà MP, Baiget M. Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene. Ann Hematol 2009; 88:951-5. [PMID: 19214511 DOI: 10.1007/s00277-009-0705-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Accepted: 01/25/2009] [Indexed: 11/29/2022]
Abstract
Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.
Collapse
Affiliation(s)
- Albert Altès
- Hematology Department, Althaia Foundation, Flor de Lis 33, 08242, Manresa, Spain.
| | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Abstract
Beta-thalassemia and sickle cell anemia (SCD) represent the most common hemoglobinopathies caused, respectively, by deficient production or alteration of the beta chain of hemoglobin (Hb). Patients affected by the most severe form of thalassemia suffer from profound anemia that requires chronic blood transfusions and chelation therapies to prevent iron overload. However, patients affected by beta-thalassemia intermedia, a milder form of the disease that does not require chronic blood transfusions, eventually also show elevated body iron content due to increased gastrointestinal iron absorption. Even SCD patients might require blood transfusions and iron chelation to prevent deleterious and painful vaso-occlusive crises and complications due to iron overload. Although definitive cures are presently available, such as bone marrow transplantation (BMT), or are in development, such as correction of the disease through hematopoietic stem cell beta-globin gene transfer, they are potentially hazardous procedures or too experimental to provide consistently safe and predictive clinical outcomes. Therefore, studies that aim to better understand the pathophysiology of the hemoglobinopathies might provide further insight and new drugs to dramatically improve the understanding and current treatment of these diseases. This review will describe how recent discoveries on iron metabolism and erythropoiesis could lead to new therapeutic strategies and better clinical care of these diseases, thereby yielding a much better quality of life for the patients.
Collapse
Affiliation(s)
- Gideon Rechavi
- Cancer Research Center, Chaim Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 52621, Israel
| | - Stefano Rivella
- Department of Pediatric Hematology-Oncology, Children’s Cancer and Blood Foundation Laboratories, Weill Medical College of Cornell University, 515 E 71 Street, S702, Box 284, New York, NY, USA
| |
Collapse
|
|
16
|
Mendes AI, Ferro A, Martins R, Picanço I, Gomes S, Cerqueira R, Correia M, Nunes AR, Esteves J, Fleming R, Faustino P. Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes. Ann Hematol 2008; 88:229-34. [PMID: 18762941 DOI: 10.1007/s00277-008-0572-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Accepted: 07/21/2008] [Indexed: 12/01/2022]
Abstract
The most frequent genotype associated with Hereditary hemochromatosis is the homozygosity for C282Y, a common HFE mutation. However, other mutations in HFE, transferrin receptor 2 (TFR2), hemojuvelin (HJV) and hepcidin (HAMP) genes, have also been reported in association with this pathology. A mutational analysis of these genes was carried out in 215 Portuguese iron-overloaded individuals previously characterized as non-C282Y or non-H63D homozygous and non-compound heterozygous. The aim was to determine the influence of these genes in the development of iron overload phenotypes in our population. Regarding HFE, some known mutations were found, as S65C and E277K. In addition, three novel missense mutations (L46W, D129N and Y230F) and one nonsense mutation (Y138X) were identified. In TFR2, besides the I238M polymorphism and the rare IVS5 -9T-->A mutation, a novel missense mutation was detected (F280L). Concerning HAMP, the deleterious mutation 5'UTR -25G-->A was found once, associated with Juvenile Hemochromatosis. In HJV, the A310G polymorphism, the novel E275E silent alteration and the novel putative splicing mutation (IVS2 +395C-->G) were identified. In conclusion, only a few number of mutations which can be linked to iron overload was found, revealing their modest contribution for the development of this phenotype in our population, and suggesting that their screening in routine diagnosis is not cost-effective.
Collapse
Affiliation(s)
- Ana Isabel Mendes
- Human Genetics Centre, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Nagayoshi Y, Nakayama M, Suzuki S, Hokamaki J, Shimomura H, Tsujita K, Fukuda M, Yamashita T, Nakamura Y, Sugiyama S, Ogawa H. A Q312X mutation in the hemojuvelin gene is associated with cardiomyopathy due to juvenile haemochromatosis. Eur J Heart Fail 2008; 10:1001-6. [PMID: 18725184 DOI: 10.1016/j.ejheart.2008.07.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2007] [Revised: 04/16/2008] [Accepted: 07/14/2008] [Indexed: 10/21/2022] Open
Abstract
BACKGROUND AND AIMS Juvenile haemochromatosis (JH) is an autosomal recessive iron disorder characterized by the early onset of secondary cardiomyopathy. The candidate modifier genes are hemojuvelin (HJV) and hepcidin antimicrobial peptide (HAMP). In the Japanese population, the prevalence of JH is quite low. The influence of HJV mutation on the JH phenotype is still unclear. METHODS AND RESULTS We searched for possible mutations in a Japanese family with 2 members who were JH patients with severe heart failure. To search for possible variants in the HJV and HAMP genes, we performed direct sequencing in the family members. A homozygous nonsense mutation in exon 4 of HJV (Q312X) was identified in the JH patients and their mother. Three individuals in the family were heterozygous for this mutation. Subsequently, we evaluated the frequency of Q312X mutation in a large population (n=361) without heart failure, using allele-specific real-time PCR assay. No Q312X mutation was detected in this population. In the patients with the homozygous HJV mutation, iron loading revealed high serum ferritin concentration with accompanying elevated transferrin iron saturation. In contrast, ferritin levels were within the normal range in individuals with the heterozygous mutation. CONCLUSIONS We found a nonsense mutation in the HJV gene. This mutation elevates ferritin levels and leads to JH associated with severe cardiomyopathy.
Collapse
Affiliation(s)
- Yasuhiro Nagayoshi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Browne SA, Reddan D. Potential role of bone morphogenetic protein (BMP) signalling as a potential therapeutic target for modification of iron balance. Nephrol Dial Transplant 2008; 24:28-30. [DOI: 10.1093/ndt/gfn551] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
|
|
19
|
Abstract
Following its identification as a liver-expressed antimicrobial peptide, the hepcidin peptide was later shown to be a key player in iron homoeostasis. It is now proposed to be the ‘iron hormone’ which, by interacting with the iron transporter ferroportin, prevents further iron import into the circulatory system. This conclusion was reached using the corresponding synthetic peptide, emphasizing the functional importance of the mature 25-mer peptide, but omitting the possible functionality of its maturation. From urine-purified native hepcidin, we recently demonstrated that a proportion of the purified hepcidin had formed iron–hepcidin complexes. This interaction was investigated further by computer modelling and, based on the sequence similarity of hepcidin with metallothionein, a three-dimensional model of hepcidin, containing one atom of iron, was constructed. To characterize these complexes further, the interaction with iron was analysed using different spectroscopic methods. Monoferric hepcidin was identified by MS, as were possibly other complexes containing two and three atoms of iron respectively, although these were present only in minor amounts. UV/visible absorbance and CD studies identified the iron-binding events which were facilitated at a physiological pH. EPR spectroscopy identified the ferric state of the bound metal, and indicated that the iron–hepcidin complex shares some similarities with the rubredoxin iron–sulfur complex, suggesting the presence of Fe3+ in a tetrahedral sulfur co-ordination. The potential roles of iron binding for hepcidin are discussed, and we propose either a regulatory function in the maturation of pro-hepcidin into active hepcidin or as the necessary link in the interaction between hepcidin and ferroportin.
Collapse
|
|
20
|
Iron regulatory and bactericidal properties of human recombinant hepcidin expressed in Pichia pastoris. Biochimie 2008; 90:726-35. [DOI: 10.1016/j.biochi.2008.01.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2007] [Accepted: 01/28/2008] [Indexed: 12/16/2022]
|
|
21
|
Nelson JE, Kowdley KV. Non-HFE hemochromatosis: genetics, pathogenesis, and clinical management. Curr Gastroenterol Rep 2008; 7:71-80. [PMID: 15701302 DOI: 10.1007/s11894-005-0069-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Recent advances in our understanding of iron metabolism and the epidemiology of iron overload disorders have shown that hereditary forms of hemochromatosis can result from mutations in several iron metabolism genes other than HFE, including Hamp, HJV, TFR2, and SCL40A. These "non-HFE" forms of hemochromatosis are much rarer than HFE-related hemochromatosis but exhibit a similar phenotype, and with the exception of ferroportin disease, a similar pattern of inheritance and parenchymal iron accumulation. Therefore, these diseases can be thought of as variant forms of a primary hepatic iron overload syndrome; thus, a unified approach can be used for evaluation and diagnosis. Management generally consists of periodic phlebotomies until iron is depleted.
Collapse
Affiliation(s)
- James E Nelson
- Department of Medicine, Division of Gastroenterology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356424, Seattle, WA 98195, USA
| | | |
Collapse
|
|
22
|
Barton JC, Acton RT, Leiendecker-Foster C, Lovato L, Adams PC, Eckfeldt JH, McLaren CE, Reiss JA, McLaren GD, Reboussin DM, Gordeuk VR, Speechley MR, Press RD, Dawkins FW, Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators. Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS study initial screening. Am J Hematol 2008; 83:126-32. [PMID: 17726683 PMCID: PMC3773364 DOI: 10.1002/ajh.21053] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25-29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25-29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire.
Collapse
Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, Alabama, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Abstract
Our concepts of hormone receptors have, until recently, been narrowly defined. In the last few years, an increasing number of reports identify novel proteins, such as enzymes, acting as receptors. In this review we cover the novel receptors for the hormones atrial naturetic hormone, enterostatin, hepcidin, thyroid hormones, estradiol, progesterone, and the vitamin D metabolites 1,25(OH)(2)D(3) and 24,25(OH)(2)D(3).
Collapse
Affiliation(s)
- Ilka Nemere
- Department of Nutrition and Food Sciences and the Center for Integrated Biosciences, Utah State University, Logan Utah, USA.
| | | |
Collapse
|
|
24
|
Abstract
Non-HFE hereditary haemochromatosis (HH) refers to a genetically heterogeneous group of iron overload disorders that are unlinked to mutations in the HFE gene. The four main types of non-HFE HH are caused by mutations in the hemojuvelin, hepcidin, transferrin receptor 2 and ferroportin genes. Juvenile haemochromatosis is an autosomal recessive disorder and can be caused by mutations in either hemojuvelin or hepcidin. An adult onset form of HH similar to HFE-HH is caused by homozygosity for mutations in transferrin receptor 2. The autosomal dominant iron overload disorder ferroportin disease is caused by mutations in the iron exporter ferroportin. The clinical characteristics and molecular basis of the various types of non-HFE haemochromatosis are reviewed. The study of these disorders and the molecules involved has been invaluable in improving our understanding of the mechanisms involved in the regulation of iron metabolism.
Collapse
Affiliation(s)
- Daniel-F Wallace
- Membrane Transport Laboratory, The Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006 Australia
| | | |
Collapse
|
|
25
|
Farnaud S, Patel A, Evans RW. Modelling of a metal-containing hepcidin. Biometals 2006; 19:527-33. [PMID: 16937259 DOI: 10.1007/s10534-005-5883-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Accepted: 12/12/2005] [Indexed: 10/24/2022]
Abstract
Hepcidin was originally identified as a liver-expressed antimicrobial peptide but further studies have shown that it also has a key role in iron homeostasis. The NMR structure of the synthetic peptides reveal a distorted beta-sheet containing 4 disulphide bridges, with an unusual vicinal disulphide bridge which has been suggested to be functionally significant. In this study, we report the presence of co-purified iron with the urine-purified 20 and 25 residue hepcidins. Since the published structure does not allow metal binding, the interaction of hepcidin with metals was investigated for other possible structural conformations by threading its primary sequence onto existing 3D folds. Several alignments were obtained and the best scores were used to build a 3D model of hepcidin containing one atom of iron. The new 3D structure, that contains only reduced Cys residues, is completely different from the solved structure of the synthetic peptide. Although the model presented here shows only one metal bound to the peptide, the binding of several metal atoms cannot be excluded from such a short flexible peptide. The co-purification of iron with both peptides, together with our 3D model, suggest a conformational polymorphism for hepcidin, reminiscent of the iron regulatory proteins IRPs.
Collapse
Affiliation(s)
- Sebastien Farnaud
- Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Hospital Campus, 3.6b New Hunt's House, London, SE1 1UL, UK.
| | | | | |
Collapse
|
|
26
|
Huang XP, O'Brien PJ, Templeton DM. Mitochondrial involvement in genetically determined transition metal toxicity. Chem Biol Interact 2006; 163:68-76. [PMID: 16797509 DOI: 10.1016/j.cbi.2006.05.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2006] [Revised: 05/11/2006] [Accepted: 05/11/2006] [Indexed: 02/03/2023]
Abstract
Iron that is not specifically chaperoned through its essential functional pathways is damaging to biological systems, in major part by catalyzing the production of reactive oxygen species. Iron serves in several essential roles in the mitochondrion, as an essential cofactor for certain enzymes of electron transport, and through its involvement in the assembly of iron-sulfur clusters and iron-porphyrin (heme) complexes, both processes occurring in the mitochondrion. Therefore, there are mechanisms that deliver iron specifically to mitochondria, although these are not well understood. Under normal circumstances the mitochondrion has levels of stored iron that are higher than other organelles, though lower than in cytosol, while in some disorders of iron metabolism, mitochondrial iron levels exceed those in the cytosol. Under these circumstances of excess iron, protective mechanisms are overwhelmed and mitochondrial damage ensues. This may take the form of acute oxidative stress with structural damage and functional impairment, but also may result in long-term damage to the mitochondrial genome. This review discusses the evidence that mitochondria do indeed accumulate iron in several genetic disorders, and are a direct target for iron toxicity when it is present in excess. We then consider two classes of genetic disorders involving iron and the mitochondrion. The first include defects in genes directly regulating mitochondrial iron metabolism that lead to Friedreich's ataxia and the various sideroblastic anemias, with excessive mitochondrial iron accumulation. Under the second class, we discuss various primary hemochromatoses that lead to direct mitochondrial damage, with reference to mutations in genes encoding HFE, hepcidin, hemojuvelin, transferrin receptor-2, ferroportin, transferrin, and ceruloplasmin.
Collapse
Affiliation(s)
- Xi-Ping Huang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ont. M5S 1A8, Canada
| | | | | |
Collapse
|
|
27
|
Fabio G, Minonzio F, Delbini P, Bianchi A, Cappellini MD. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood 2006; 109:362-4. [PMID: 16960153 DOI: 10.1182/blood-2006-04-016949] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder of iron metabolism, genetically heterogeneous. In JH, symptomatic organ involvement occurs as early as the second decade of life. Heart failure and/or arrhythmias are the most frequent causes of death. Phlebotomy is the safest, most effective, and most economic therapeutic approach in hemochromatosis patients but is not indicated during the treatment of severe congestive heart failure with unstable hemodynamic status. The treatment of iron overload in these prohibitive clinical situations has to be carried out using iron chelators. We report a case of heart failure in the setting of unrecognized juvenile hemochromatosis successfully treated by the simultaneous administration of deferoxamine and deferiprone. To our knowledge, this is the first patient affected by JH treated with combined chelation regimen.
Collapse
Affiliation(s)
- Giovanna Fabio
- Department of Internal Medicine, Università degli Studi di Milano and Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy.
| | | | | | | | | |
Collapse
|
|
28
|
Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl) 2006; 84:349-64. [PMID: 16604332 PMCID: PMC7095819 DOI: 10.1007/s00109-005-0029-x] [Citation(s) in RCA: 168] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2004] [Accepted: 10/21/2005] [Indexed: 02/07/2023]
Abstract
Excessive body iron or iron overload occurs under conditions such as primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis), which are reaching epidemic levels worldwide. Primary hemochromatosis is the most common genetic disorder with an allele frequency greater than 10% in individuals of European ancestry, while hemosiderosis is less common but associated with a much higher morbidity and mortality. Iron overload leads to iron deposition in many tissues especially the liver, brain, heart and endocrine tissues. Elevated cardiac iron leads to diastolic dysfunction, arrhythmias and dilated cardiomyopathy, and is the primary determinant of survival in patients with secondary iron overload as well as a leading cause of morbidity and mortality in primary hemochromatosis patients. In addition, iron-induced cardiac injury plays a role in acute iron toxicosis (iron poisoning), myocardial ischemia–reperfusion injury, Friedreich ataxia and neurodegenerative diseases. Patients with iron overload also routinely suffer from a range of endocrinopathies, including diabetes mellitus and anterior pituitary dysfunction. Despite clear connections between elevated iron and clinical disease, iron transport remains poorly understood. While low-capacity divalent metal and transferrin-bound transporters are critical under normal physiological conditions, L-type Ca2+ channels (LTCC) are high-capacity pathways of ferrous iron (Fe2+) uptake into cardiomyocytes especially under iron overload conditions. Fe2+ uptake through L-type Ca2+ channels may also be crucial in other excitable cells such as pancreatic beta cells, anterior pituitary cells and neurons. Consequently, LTCC blockers represent a potential new therapy to reduce the toxic effects of excess iron.
Collapse
Affiliation(s)
- Gavin Y. Oudit
- Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
- Departments of Medicine and Physiology, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
- Division of Cardiology and the Division of Cellular and Molecular Biology, University Health Network, University of Toronto, Ontario, Canada M5S 3E2
- Heart and Stroke/Richard Lewar Centre of Excellence, 150 College Street, Rm 68, Fitzgerald Building, Toronto, Ontario Canada M5S 3E2
| | - Maria G. Trivieri
- Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
- Departments of Medicine and Physiology, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
| | - Neelam Khaper
- Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
| | - Peter P. Liu
- Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
- Departments of Medicine and Physiology, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
| | - Peter H. Backx
- Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
- Departments of Medicine and Physiology, University Health Network, University of Toronto, Ontario, M5S 3E2 Canada
- Division of Cardiology and the Division of Cellular and Molecular Biology, University Health Network, University of Toronto, Ontario, Canada M5S 3E2
- Heart and Stroke/Richard Lewar Centre of Excellence, 150 College Street, Rm 68, Fitzgerald Building, Toronto, Ontario Canada M5S 3E2
| |
Collapse
|
|
29
|
Affiliation(s)
- Peter F Whitington
- Department of Pediatrics, Northwestern University Feinberg Medical School, Children's Memorial Hospital, Chicago, IL, USA.
| |
Collapse
|
|
30
|
Abstract
Summary Hepcidin is an important and recently discovered regulator of iron homeostasis. There is strong evidence in support of an important role for hepcidin dysregulation in the pathogenesis of iron overload disorders, and possibly in the aetiology of the anaemia of chronic disease. Further research is needed into the physiology of hepcidin to elucidate the relative contributions of the liver and kidney to its production and metabolism. The study of the differential roles of prohepcidin and its metabolites as well as the significance of their serum and urine levels will enhance our understanding of their role in iron metabolism.
Collapse
Affiliation(s)
- A Hugman
- Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
| |
Collapse
|
|
31
|
Daraio F, Ryan E, Gleeson F, Roetto A, Crowe J, Camaschella C. Juvenile hemochromatosis due to G320V/Q116X compound heterozygosity of hemojuvelin in an Irish patient. Blood Cells Mol Dis 2006; 35:174-6. [PMID: 15967692 DOI: 10.1016/j.bcmd.2005.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2005] [Accepted: 02/03/2005] [Indexed: 11/30/2022]
Abstract
Hemojuvelin (HJV) is a recently discovered gene responsible for 1q-linked juvenile hemochromatosis. The majority of mutations characterized in this gene are rare and private, except G320V, identified in patients from different countries. Here, we report the clinical features and the molecular study of a young Irish patient presenting with severe cardiac disease related to iron overload. We sequenced the coding region and the exon-intron boundaries of genes associated with juvenile hemochromatosis, HAMP and HJV encoding hepcidin and hemojuvelin respectively. Two heterozygous HJV mutations were identified: the G320V mutation and the new Q116X mutation that cause a premature stop codon in the protein. This finding increases the number of mutations identified in HJV gene and underlines that the G320V is a recurrent mutation, even in Northern Europe.
Collapse
Affiliation(s)
- F Daraio
- Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Azienda Ospedaliera San Luigi, Orbassano, Torino, Italy
| | | | | | | | | | | |
Collapse
|
|
32
|
Abstract
The molecular basis of haemochromatosis has proved more complex than expected. After the 1996 identification of the main causative gene HFE and confirmation that most patients were homozygous for the founder C282Y mutation, it became clear that some families were linked to rarer conditions, first named 'non-HFE haemochromatosis'. The genetics of these less common forms was intensively studied between 2000 and 2004, leading to the recognition of haemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin-related haemochromatosis, and opening the way for novel hypotheses such as those related to digenic modes of inheritance or the involvement of modifier genes. Molecular studies of rare haemochromatosis disorders have contributed to our understanding of iron homeostasis. In turn, recent findings from studies of knockout mice and functional studies have confirmed that HAMP plays a central role in mobilization of iron, shown that HFE, TFR2 and HJV modulate HAMP production according to the body's iron status, and demonstrated that HAMP negatively regulates cellular iron efflux by affecting the ferroportin cell surface availability. These data shed new light on the pathophysiology of all types of haemochromatosis, and offer novel opportunities to comment on phenotypic differences and distinguish mutations.
Collapse
|
|
33
|
Abstract
There is increasing evidence that moderately elevated body iron stores, below levels commonly found in genetic hemochromatosis, may be associated with adverse health outcomes. Genetic hemochromatosis, characterized by transferrin saturation (TS) greater than 45%, is most often linked to homozygosity of the HFE C282Y allele. The phenotype is also modulated by mutations of more recently discovered genes (including ferroportin, hemojuvelin, hepcidin, and transferrin receptor) and environmental factors (including alcohol, viruses, diet, blood loss). Iron overload without hemochromatosis is characterized by high levels of serum ferritin and normal TS, as seen in dysmetabolic hepatosiderosis. Elevated serum ferritin levels predict incident type 2 diabetes in prospective studies and have been associated with hypertension, dyslipidemia, glucose tolerance disturbances, central adiposity, and metabolic syndrome. High ferritin levels are not synonymous with iron overload and may in some cases be a simple marker of insulin resistance.
Collapse
Affiliation(s)
- M-C Vantyghem
- Service d'endocrinologie et métabolisme, CHU, Lille.
| | | | | | | |
Collapse
|
|
34
|
Porto G, Roetto A, Daraio F, Pinto JP, Almeida S, Bacelar C, Nemeth E, Ganz T, Camaschella C. A Portuguese patient homozygous for the -25G>A mutation of the HAMP promoter shows evidence of steady-state transcription but fails to up-regulate hepcidin levels by iron. Blood 2005; 106:2922-3. [PMID: 16204153 DOI: 10.1182/blood-2005-04-1630] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
|
35
|
Abstract
Mutations in the hepcidin gene HAMP and the hemojuvelin gene HJV have recently been shown to result in juvenile haemochromatosis (JH). Hepcidin is an antimicrobial peptide that plays a key role in regulating intestinal iron absorption. Hepcidin levels are reduced in patients with haemochromatosis due to mutations in the HFE and HJV genes. Digenic inheritance of mutations in HFE and HAMP can result in either JH or hereditary haemochromatosis (HH) depending upon the severity of the mutation in HAMP. Here we review these findings and discuss how understanding the different types of haemochromatosis and our increasing knowledge of iron metabolism may help to elucidate the host's response to infection.
Collapse
|
|
36
|
Zoller H, McFarlane I, Theurl I, Stadlmann S, Nemeth E, Oxley D, Ganz T, Halsall DJ, Cox TM, Vogel W. Primary iron overload with inappropriate hepcidin expression in V162del ferroportin disease. Hepatology 2005; 42:466-72. [PMID: 15986403 DOI: 10.1002/hep.20775] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Ferroportin disease (hemochromatosis type 4) is a recently recognized disorder of human iron metabolism, characterized by iron deposition in macrophages, including Kupffer cells. Mutations in the gene encoding ferroportin 1, a cellular iron exporter, are responsible for this iron storage disease, inherited as an autosomal dominant trait. We present clinical, histopathological, and radiological findings in a family with the most common ferroportin mutation, V162del. In the index case, the disorder is characterized by abundant deposition of hemosiderin in all tissues investigated (mesenteric lymph node, liver, gastric and duodenal mucosa, and also in squamous cell carcinoma of the lung). The radiological findings indicated the presence of excess iron in bone marrow and spleen. Despite a significant burden of iron, no features of chronic liver disease were found in affected members of the family, including individuals aged up to 80 years. Hyperferritinemia greater than 1,000 microg/L was a penetrant biochemical finding before the second decade in life and was associated with significantly increased serum concentrations of pro-hepcidin that correlated positively with urinary hepcidin concentrations. In conclusion, the systemic iron burden in ferroportin disease is not a sufficient cause for chronic liver disease. In patients with most, but not all, ferroportin mutations, retention of iron in macrophages of the liver and other organs may protect against damage to parenchymal cells. Finally, macrophage iron storage in ferroportin disease is associated with elevated serum pro-hepcidin levels.
Collapse
Affiliation(s)
- Heinz Zoller
- Clinical Division of Gastroenterology and Hepatology, Innsbruck Medical University, Innsbruck, Austria.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 2005; 106:3710-7. [PMID: 16030190 DOI: 10.1182/blood-2005-05-1857] [Citation(s) in RCA: 136] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Genetic analysis of hemochromatosis has led to the discovery of a number of genes whose mutations disrupt iron homeostasis and lead to iron overload. The introduction of molecular tests into clinical practice has provided a tool for early diagnosis of these conditions. It has become clear that hemochromatosis includes a spectrum of disorders that range from simple biochemical abnormalities to chronic asymptomatic tissue damage in midlife to serious life-threatening diseases in young subjects. Molecular studies have identified the systemic loop that controls iron homeostasis and is centered on the hepcidin-ferroportin interaction. The complexity of this regulatory pathway accounts for the genetic heterogeneity of hemochromatosis and related disorders and raises the possibility that genes encoding components of the pathway may be modifiers of the main genotype. Molecular diagnosis has improved the classification of the genetic conditions leading to iron overload and identified novel entities, characterized by both iron loading and variable degrees of anemia. Despite the progress in the diagnosis, classification, and mechanisms of iron overload disorders, the treatment of affected patients continues to rely on regular phlebotomy. Understanding the molecular circuitry of iron control may lead to the identification of potential therapeutic targets for novel treatment strategies to be used in association with or as an alternative to phlebotomy.
Collapse
Affiliation(s)
- Clara Camaschella
- Università Vita-Salute and Istituto di Ricovero e Cura a Carratere Scientifico Ospedale San Raffaele, Via Olgettina, 60, 20132 Milano, Italy.
| |
Collapse
|
|
38
|
Abstract
Elucidation of the molecular pathways of iron transport through cells and its control is leading to an understanding of genetic iron loading conditions. The general phenotype of haemochromatosis is iron accumulation in liver parenchymal cells, a raised serum transferrin saturation and ferritin concentration. Four types have been identified: type 1 is the common form and is an autosomal recessive disorder of low penetrance strongly associated with mutations in the HFE gene on chromosome 6(p21.3); type 2 (juvenile haemochromatosis) is autosomal recessive, of high penetrance with causative mutations identified in the HFE2 gene on chromosome 1 (q21) and the HAMP gene on chromosome 19 (q13); type 3 is also autosomal recessive with mutations in the TfR2 gene on chromosome 3 (7q22); type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene. In type 4, iron accumulates in both parenchymal and reticuloendothelial cells and the transferrin saturation may be normal. There are also inherited neurodegenerative conditions associated with iron accumulation. The current research challenges include understanding the central role of the HAMP gene (hepcidin) in controlling iron absorption and the reasons for the variable penetrance in HFE type 1.
Collapse
Affiliation(s)
- Mark Worwood
- Department of Haematology, University of Wales College of Medicine, Cardiff CF14 4XN, Wales, UK.
| |
Collapse
|
|
39
|
Cadet E, Perez AS, Capron D, Rochette J. Bases moléculaires des hémochromatoses génétiques. Rev Med Interne 2005; 26:393-402. [PMID: 15893030 DOI: 10.1016/j.revmed.2004.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2004] [Accepted: 09/16/2004] [Indexed: 10/26/2022]
Abstract
PURPOSE Recent discoveries in molecular mechanisms of iron metabolism have changed the classical view of hereditary iron overload conditions. We present natural mutations in newly discovered genes and related phenotypes observed in patients with different form of haemochromatosis. CURRENT KNOWLEDGE AND KEY POINTS Most haemochromatosis patients are homozygous for the C282Y mutation in the HFE gene. Ferroportin, TFR2, hemojuvelin and hepcidin mutations also cause iron overload. Recent data support the hypothesis that haemochromatosis should no longer be considered a monogenic disease but rather an oligogenic disorder. Several results suggest that haemochromatosis could result from digenic inheritance of mutations in HFE and HAMP. FUTURE PROSPECTS AND PROJECTS Other modifier genes probably influence penetrance in C282Y homozygous patients. Such genes could enhance or reduce the phenotypic expression in various iron overload conditions.
Collapse
Affiliation(s)
- E Cadet
- Service de génétique moléculaire médicale et UPRES EA 2629, CHU d'Amiens, université de Picardie-Jules-Verne, 3, rue des Louvels, 80036 Amiens cedex, France.
| | | | | | | |
Collapse
|
|
40
|
Lou DQ, Lesbordes JC, Nicolas G, Viatte L, Bennoun M, Van Rooijen N, Kahn A, Renia L, Vaulont S. Iron- and inflammation-induced hepcidin gene expression in mice is not mediated by Kupffer cells in vivo. Hepatology 2005; 41:1056-64. [PMID: 15793843 DOI: 10.1002/hep.20663] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepcidin, a recently discovered iron regulatory peptide, is believed to inhibit the release of iron from absorptive enterocytes and macrophages. Liver hepcidin synthesis is induced in vivo by iron stores and inflammation. The molecular basis of the regulation of hepcidin gene expression by these effectors in hepatocytes is currently unknown, although there is strong evidence that indirect mechanisms are involved. The aims of this study were to gain insight into these mechanisms and to determine to what extent other liver cell types are responsible for transducing the signal by which hepcidin expression is regulated in mouse hepatocytes. For this, we depleted Kupffer cells by injection of liposome-encapsulated clodronate and then studied iron- and inflammation-induced hepcidin gene expression. In addition, we directly evaluated the role of the inflammatory cytokine interleukin 6 (IL-6) by using IL-6-deficient mice. Our results show that iron is able to induce hepcidin gene expression independently of Kupffer cells in the liver and circulating IL-6. In contrast, we show that hepcidin gene induction by inflammation is also independent of Kupffer cells, but involves, at least partly, IL-6. In conclusion, these results show that two independent regulatory pathways control hepcidin gene expression and suggest that hepatocytes play a key role in the regulation of hepcidin gene expression by sensing iron and inflammatory signals.
Collapse
Affiliation(s)
- Dan-Qing Lou
- Département de Génétique, Développement et Pathologie Moléculaire, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, et Université René Descartes, Faculté de Médecine Cochin-Port Royal, Paris, France
| | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Brissot P, Jouanolle AM, Le Lan C, Loreal O, Deugnier Y, David V. Surcharges héréditaires en fer non liées à HFE. ACTA ACUST UNITED AC 2005; 29:565-8. [PMID: 15980752 DOI: 10.1016/s0399-8320(05)82130-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
42
|
Biasiotto G, Roetto A, Daraio F, Polotti A, Gerardi GM, Girelli D, Cremonesi L, Arosio P, Camaschella C. Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele. Blood Cells Mol Dis 2005; 33:338-43. [PMID: 15528154 DOI: 10.1016/j.bcmd.2004.08.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2004] [Revised: 08/06/2004] [Indexed: 02/09/2023]
Abstract
HFE-hemochromatosis is the most common form of hereditary hemochromatosis. The disorder is associated with the homozygous C282Y mutation and has variable phenotype, being modulated by environmental and genetic factors. Candidate modifier genes are hemojuvelin and hepcidin, which are responsible for juvenile hemochromatosis. We used DHPLC to scan mutations in these genes in a cohort of unrelated patients with C282Y mutation. They consisted of 136 C282Y homozygous, 43 heterozygous, and 42 C282Y/H63D compound heterozygous, plus 62 controls subjects. Mutations and polymorphisms were found in 16 patients and 4 controls. Abnormally high indices of iron status were found in subjects C282Y/H63D heterozygous for the N196K hemojuvelin mutation and the -72C > T hepcidin substitution. The already described G71D mutation of hepcidin did not induce evident modification of the C282Y/H63D phenotype. The data show that heterozygous mutations of the hemojuvelin gene contribute like those of hepcidin to the phenotypic heterogeneity of hemochromatosis. However, they are rare and explain only a minor portion of the variable penetrance of the disorder.
Collapse
Affiliation(s)
- Giorgio Biasiotto
- Dipartimento Materno Infantile e Tecnologie Biomediche, Università di Brescia, A.O. Spedali Civili, Brescia, Italy
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Filali M, Le Jeunne C, Durand E, Grinda JM, Roetto A, Daraio F, Bruneval P, Jeunemaitre X, Gimenez-Roqueplo AP. Juvenile hemochromatosis HJV-related revealed by cardiogenic shock. Blood Cells Mol Dis 2005; 33:120-4. [PMID: 15315789 DOI: 10.1016/j.bcmd.2004.05.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2004] [Revised: 05/19/2004] [Indexed: 11/22/2022]
Abstract
Hemochromatosis is a heterogeneous genetic disease. Juvenile hemochromatosis is a severe rare recessive autosomal disease. Herein, we report a consanguineous family linked to a mutation in the recently identified HJV gene. A refractory cardiogenic shock had revealed hemochromatosis in the proband, a 26-year-old woman, and led to the death by heart failure. Regular phlebotomies in her young sister, which was also affected, had allowed to prevent the severe complications of the disease. These two affected subjects presented an identical homozygous haplotype at the 1q21 chromosome region and a missense homozygous mutation at the HJV gene (Arg288 > Trp). This observation underlines the importance of HJV genetic testing, by complete screening of the gene, in young patients with abnormal iron parameters and hypogonadism and/or cardiac symptoms to prevent death from cardiac complications.
Collapse
Affiliation(s)
- Mounir Filali
- Département de Génétique Moléculaire, Hôpital Européen Georges Pompidou, Assistance Publique/Hôpitaux de Paris, Paris, France
| | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Jánosi A, Andrikovics H, Vas K, Bors A, Hubay M, Sápi Z, Tordai A. Homozygosity for a novel nonsense mutation (G66X) of the HJV gene causes severe juvenile hemochromatosis with fatal cardiomyopathy. Blood 2005; 105:432. [PMID: 15611318 DOI: 10.1182/blood-2004-09-3508] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
|
|
45
|
Lorenz M, Kletzmayr J, Huber A, Hörl WH, Sunder-Plassmann G, Födinger M. Iron overload in kidney transplants: Prospective analysis of biochemical and genetic markers. Kidney Int 2005; 67:691-7. [PMID: 15673318 DOI: 10.1111/j.1523-1755.2005.67129.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND The prevalence of iron overload and the influence of mutations in the HFE and TRF2 gene on biochemical markers of iron overload among renal transplant patients is unknown. METHODS Serum iron, ferritin, transferrin saturation (TSAT), and liver function parameters were analyzed in a cohort of 438 renal transplants. In patients with iron overload, the time course of biochemical markers of iron status as well as the influence of iron loading mutations was investigated during a time period of 5 years. RESULTS Of 438 renal transplant patients 41 (9.4%) presented with an iron loading phenotype (TSAT above 40% and/or ferritin above 800 ng/mL). Mutations in the HFE gene were present in 12 of 33 (36.3%) patients with iron overload. Among these one patient was homozygous for HFE C282Y, and two patients were compound heterozygous for HFE C282Y/H63D. No individual tested positive for nine other mutations in HFE as well as theTRF2 Y250X mutation. Over time we observed a decrease of mean iron and ferritin levels, and of mean TSAT in our study sample. In patients with mutations in HFE this decrease was less pronounced as compared to patients without mutations. We found an independent positive association between the presence of mutations in HFE and serum alanine-aminotransferase levels at follow-up (P= 0.003). CONCLUSION Our study demonstrates that iron overload is frequently present in renal transplant patients and shows a continuous decrease over time. This decrease is possibly impaired by the HFE C282Y and HFE H63D mutations. Furthermore, mutations in HFE may influence liver function as reflected by increased alanine-aminotransferase concentrations.
Collapse
Affiliation(s)
- Matthias Lorenz
- Division of Nephrology and Dialysis, Department of Medicine III, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria
| | | | | | | | | | | |
Collapse
|
|
46
|
Matthes T, Aguilar-Martinez P, Pizzi-Bosman L, Darbellay R, Rubbia-Brandt L, Giostra E, Michel M, Ganz T, Beris P. Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5′-UTR of the HAMP gene. Blood 2004; 104:2181-3. [PMID: 15198949 DOI: 10.1182/blood-2004-01-0332] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Juvenile hereditary hemochromatosis is a genetically heterogeneous disorder transmitted as an autosomal recessive trait. It is most often caused by mutations in the HJV gene and rarely in the HAMP gene. Hepcidin is considered to constitute a negative regulator of iron absorption, and its production is increased in inflammatory states and iron overload. We report the detection of a new mutation in the HAMP gene leading to juvenile hemochromatosis in 2 members of a Portuguese family. The mutation lies in the 5′-UTR (untranslated region) of the gene and creates a new initiation codon in the context of a Kozak sequence. We found no trace of hepcidin protein in the patients' urine, suggesting that ribosomes select the mutant initiation codon for translation. The decrease of hepcidin production would thus lead to increased iron absorption, resulting in iron deposition in parenchymal tissues. Phlebotomy therapy of the 2 patients resulted in impressive clinical improvement. (Blood. 2004;104: 2181-2183)
Collapse
Affiliation(s)
- Thomas Matthes
- Division of Hematology, University Hospital, Geneva, Switzerland.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Huang FW, Rubio-Aliaga I, Kushner JP, Andrews NC, Fleming MD. Identification of a novel mutation (C321X) in HJV. Blood 2004; 104:2176-7. [PMID: 15138164 DOI: 10.1182/blood-2004-01-0400] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Abstract
Juvenile hemochromatosis is a rare autosomal recessive disorder characterized by the early onset of severe iron overload. We report the occurrence of compound heterozygous mutations in hemojuvelin (HJV), including a termination codon, in a patient with juvenile hemochromatosis but no family history of iron disorders. (Blood. 2004;104:2176-2177)
Collapse
Affiliation(s)
- Franklin W Huang
- Division of Medical Sciences, Harvard University, Boston, MA, USA
| | | | | | | | | |
Collapse
|
|
48
|
Beutler L, Beutler E. Hematologically important mutations: iron storage diseases. Blood Cells Mol Dis 2004; 33:40-4. [PMID: 15223009 DOI: 10.1016/j.bcmd.2004.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2004] [Indexed: 11/19/2022]
Affiliation(s)
- Lisa Beutler
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | | |
Collapse
|
|
49
|
Krijt J, Cmejla R, Sýkora V, Vokurka M, Vyoral D, Necas E. Different expression pattern of hepcidin genes in the liver and pancreas of C57BL/6N and DBA/2N mice. J Hepatol 2004; 40:891-6. [PMID: 15158327 DOI: 10.1016/j.jhep.2004.02.029] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2003] [Revised: 02/13/2004] [Accepted: 02/18/2004] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Male C57BL/6 and DBA/2 mice differ in their liver iron content. The aim of this study was to examine possible differences in the expression of hepcidin genes (Hamp and Hamp2) between the two strains. METHODS Hepatic mRNAs were quantified by real-time PCR. RESULTS Ferroportin1, transferrin receptor 2 and HAMP mRNA levels displayed no significant strain differences. However, HAMP2 mRNA levels were higher in DBA/2N mice. In both strains, HAMP2 mRNA content was sex-dependent, with higher values in female animals. Both hepatic HAMP and HAMP2 mRNA levels were elevated by iron overload, but treatment with lipopolysaccharide increased only HAMP mRNA. Lipopolysaccharide also elevated the amount of HAMP mRNA in the pancreas, while pancreatic HAMP2 mRNA levels were decreased. Sequence analysis of hepcidin amplicons from DBA/2N mice predicted an Asn-->Lys substitution at position 73 of the HAMP peptide and a Ser-->Phe substitution at position 76 of the HAMP2 peptide. CONCLUSIONS Hepatic Hamp2 expression displays considerable strain- and sex-dependent variation. Lipopolysaccharide increases expression of Hamp both in the liver and pancreas, but Hamp2 does not respond to lipopolysaccharide treatment. The significance of the amino acid substitutions in hepcidin peptides in DBA/2N mice is at present unknown.
Collapse
Affiliation(s)
- Jan Krijt
- Institute of Pathophysiology, First Medical Faculty, Charles University, U nemocnice 5, 128 53 Prague, Czech Republic.
| | | | | | | | | | | |
Collapse
|