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DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway. Hepatol Int 2023; 17:648-661. [PMID: 36729283 DOI: 10.1007/s12072-022-10474-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/24/2022] [Indexed: 02/03/2023]
Abstract
PURPOSE Pathogenic variants in HFE and non-HFE genes have been identified in hereditary hemochromatosis (HH) in different patient populations, but there are still a considerable proportion of patients with unexplained primary iron overload. We recently identified in Chinese patients with unexplained primary iron overload a recurrent p.L708V variant in the differentially expressed in normal and neoplastic cells domain 3 (DENND3) gene, functioning as a guanine nucleotide exchange factor for small GTpase Rab12 which down-regulates TfR expression in mice. We aim to investigate the pathogenicity and the underlying mechanism of the DENND3 p.L708V variant in HH patients. METHODS Patients with primary iron overload were analyzed for DENND3 p.L708V. TFR2 and hepcidin expression in livers were examined in HH patients harboring DENND3 p.L708V. The effects of DENND3 p.L708V on RAB12/TFR2 and downstream iron metabolic pathways were investigated in vitro and in vivo. RESULTS Six of 31 patients with HH (19.35%) harbored the DENND3 p.L708V variant. The expression of TFR2 and hepcidin was decreased in the liver of HH patients with DENND3 p.L708V. Cells transfected with the DENND3 p.L708V vector showed up-regulation of RAB12 expression and TFR2 degradation in lysosomes, and down-regulation of the pSMAD1/5 and hepcidin. Mice models infected with adeno-associated virus expressing DENND3 p.L708V variant showed higher total serum iron concentrations and decreased HAMP level, increased amount of iron accumulation and the down-regulated of TFR2 expression in the liver. CONCLUSIONS The DENND3 p.L708V activating variant down-regulates hepcidin expression through the DENND3/RAB12/TFR2 axis, which may represent a potential novel pathogenic factor of HH.
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Zoller H, Schaefer B, Vanclooster A, Griffiths B, Bardou-Jacquet E, Corradini E, Porto G, Ryan J, Cornberg M. EASL Clinical Practice Guidelines on haemochromatosis. J Hepatol 2022; 77:479-502. [PMID: 35662478 DOI: 10.1016/j.jhep.2022.03.033] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 03/29/2022] [Indexed: 12/15/2022]
Abstract
Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT >45% and ferritin >200 μg/L in females and TSAT >50% and ferritin >300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin <50 μg/L during the induction phase and <100 μg/L during the maintenance phase.
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Juvenile Hemochromatosis due to a Homozygous Variant in the HJV Gene. Case Rep Pediatr 2022; 2022:7743748. [PMID: 35449524 PMCID: PMC9017560 DOI: 10.1155/2022/7743748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 12/30/2022] Open
Abstract
Hemochromatosis type 2 or juvenile hemochromatosis has an early onset of severe iron overload resulting in organ manifestation such as liver fibrosis, cirrhosis, cardiomyopathy, arthropathy, hypogonadism, diabetes, osteopathic medicine, and thyroid abnormality, before age of 30. Juvenile hemochromatosis type 2a and 2b is an autosomal recessive disease caused by pathogenic variants in HJV and HAMP genes, respectively. We report a child with hepatic iron overload and family history of hemochromatosis. We aim to raise awareness of juvenile hemochromatosis, especially in families with a positive family history, as early diagnosis and treatment may prevent organ involvement and end-stage disease. The purpose of this study was to identify the gene variant that causes the disease. The genetic study was performed with a targeted gene panel: HFE, HJV, HAMP, TFR2, SLC40A1, FTL, and FTH1. We identified the variant c.309C > G (p.Phe103Leu) in the HJV gene in the homozygous state in the patient.
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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.
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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
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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.
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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
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Juvenile Hemochromatosis: A Case Report and Review of the Literature. Pharmaceuticals (Basel) 2020; 13:ph13080195. [PMID: 32824233 PMCID: PMC7465211 DOI: 10.3390/ph13080195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022] Open
Abstract
Juvenile hemochromatosis (JH), type 2A hemochromatosis, is a rare autosomal recessive disorder of systemic iron overload due to homozygous mutations of HJV (HFE2), which encodes hemojuvelin, an essential regulator of the hepcidin expression, causing liver fibrosis, diabetes, and heart failure before 30 years of age, often with fatal outcomes. We report two Japanese sisters of 37 and 52 years of age, with JH, who showed the same homozygous HJV I281T mutation and hepcidin deficiency and who both responded well to phlebotomy on an outpatient basis. When all reported cases of JH with homozygous HJV mutations in the relevant literature were reviewed, we found—for the first time—that JH developed in females and males at a ratio of 3:2, with no age difference in the two groups. Furthermore, we found that the age of onset of JH may depend on the types of HJV mutations. In comparison to patients with the most common G320V/G320V mutation, JH developed earlier in patients with L101P/L101P or R385X/R385X mutations and later in patients with I281T/I281T mutations.
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Piperno A, Pelucchi S, Mariani R. Inherited iron overload disorders. Transl Gastroenterol Hepatol 2020; 5:25. [PMID: 32258529 DOI: 10.21037/tgh.2019.11.15] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/12/2019] [Indexed: 12/21/2022] Open
Abstract
Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.
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Affiliation(s)
- Alberto Piperno
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Centre for Rare Diseases, Disorder of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy
| | - Sara Pelucchi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Raffaella Mariani
- Centre for Rare Diseases, Disorder of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy
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Koshy A, Mukkada RJ, Chettupuzha AP, Francis JV, Kandathil JC, Mahadevan P. Hemochromatosis in India: First Report of Whole Exome Sequencing With Review of the Literature. J Clin Exp Hepatol 2020; 10:163-169. [PMID: 32189932 PMCID: PMC7067988 DOI: 10.1016/j.jceh.2019.04.051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 04/17/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Primary hemochromatosis is unusual in India. The homeostatic iron regulator (HFE) gene C282Y mutation, a common cause for hemochromatosis in Europe, is considered almost nonexistent in India. We are reporting a case of hemochromatosis with the HFE gene C282Y mutation and two other adult cases with a novel hemojuvelin (HJV) mutation from Kerala. METHODS Of 434 cases with chronic liver disease, 3 cases were identified with the serum ferritin level of more than 1000 ng/mL and primary hemochromatosis after excluding secondary causes. Whole exome sequencing, including genes HFE, HJV, SLC40A1, TFR2, FTH1, HAMP, SKIV2L, TTC37, and BMP2, was performed for blood samples in all 3 cases. RESULTS One patient with hemochromatosis had a homozygous HFE gene C282Y mutation, and two other adult cases had a novel homozygous HJV D355Y mutation. This is the first report of hemochromatosis associated with the HFE C282Y mutation from Kerala and the second report in India. This is the second report of hemochromatosis associated with an HJV mutation from India. CONCLUSION HJV mutations may explain some of the adult onset primary hemochromatosis in India.
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Affiliation(s)
- Abraham Koshy
- Departments of Gastroenterology, VPS Lakeshore Hospital, Kochi, India
- Address for correspondence: Professor Abraham Koshy, Department of Gastroenterology Lakeshore Hospital, Kochi 682304, India. Tel: +91 484 701032; fax: +91 484 701996.
| | - Roy J. Mukkada
- Departments of Gastroenterology, VPS Lakeshore Hospital, Kochi, India
| | | | - Jose V. Francis
- Departments of Gastroenterology, VPS Lakeshore Hospital, Kochi, India
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Kawaguchi T, Ikuta K, Tatsumi Y, Toki Y, Hayashi H, Tonan T, Ohtake T, Hoshino S, Naito M, Kato K, Okumura T, Torimura T. Identification of heterozygous p.Y150C and p.V274M mutations in the HJV gene in a Japanese patient with a mild phenotype of juvenile hemochromatosis: A case report. Hepatol Res 2020; 50:144-150. [PMID: 31472034 DOI: 10.1111/hepr.13423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 08/07/2019] [Accepted: 08/20/2019] [Indexed: 12/08/2022]
Abstract
Juvenile hemochromatosis (JH) is known as a progressive iron-storage disease, and causes severe organ impairments, including cardiomyopathy and liver cirrhosis. However, JH is a rare genetic disorder, and information for genetic mutations and phenotypes is limited. Here, we report a case of JH with heterozygous p.Y150C and p.V274M mutations in the HJV gene. A 39-year-old Japanese man was referred to Kurume University Hospital, Kurume, Japan, for fatigue and liver injury, which first appeared at the age of 25 years. There was no history of alcohol abuse and medication, and viral hepatitis, autoimmune liver diseases, and Wilson's disease were absent. However, transferrin saturation, serum ferritin, and fasting serum hepcidin levels were 98.4%, 6421 ng/mL, and 7.4 ng/mL, respectively. Furthermore, a marked reduction in signal intensity of the liver in T1/T2-weighted magnetic resonance images was seen and the R2* maps showed hepatic iron overload. Family history of hemochromatosis and severe organ impairment, such as cardiac dysfunction and diabetes mellitus, were negative. In addition, the HFE and HAMP genes did not show any mutation. However, we identified novel heterozygous p.Y150C and p.V274M mutations in the HJV gene in the patient. The p.Y150C and p.V274M mutations were seen in his mother and father, respectively. After phlebotomy, fatigue disappeared and serum transaminase levels were normalized. Furthermore, R2* maps showed a reduction of hepatic iron concentration. We first demonstrated heterozygous p.Y150C and p.V274M mutations in the HJV gene of patients with a mild JH phenotype. Thus, genetic testing should be considered even in patients with a mild phenotype of hemochromatosis.
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Affiliation(s)
- Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Katsuya Ikuta
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yasuaki Tatsumi
- Laboratory of Medicine, Aichi-Gakuin University, School of Pharmacy, Nagoya, Japan
| | - Yasumichi Toki
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Hisao Hayashi
- Laboratory of Medicine, Aichi-Gakuin University, School of Pharmacy, Nagoya, Japan
| | - Tatsuyuki Tonan
- Department of Radiology, Kurume University School of Medicine, Kurume, Japan
| | - Takaaki Ohtake
- Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Japan
| | | | | | - Koichi Kato
- Laboratory of Medicine, Aichi-Gakuin University, School of Pharmacy, Nagoya, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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Kong X, Xie L, Zhu H, Song L, Xing X, Yang W, Chen X. Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review. Orphanet J Rare Dis 2019; 14:171. [PMID: 31286966 PMCID: PMC6615163 DOI: 10.1186/s13023-019-1097-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 05/19/2019] [Indexed: 12/12/2022] Open
Abstract
Hereditary hemochromatosis (HH) is a genetic disorder that causes excess absorption of iron and can lead to a variety of complications including liver cirrhosis, arthritis, abnormal skin pigmentation, cardiomyopathy, hypogonadism, and diabetes. Hemojuvelin (HJV) is the causative gene of a rare subtype of HH worldwide. This study aims to systematically review the genotypic and phenotypic spectra of HJV-HH in multiple ethnicities, and to explore the genotype-phenotype correlations. A comprehensive search of PubMed database was conducted. Data were extracted from 57 peer-reviewed original articles including 132 cases with HJV-HH of multiple ethnicities, involving 117 biallelic cases and 15 heterozygotes. Among the biallelic cases, male and female probands of Caucasian ancestry were equally affected, whereas males were more often affected among East Asians (P=1.72×10-2). Hepatic iron deposition and hypogonadism were the most frequently reported complications. Hypogonadism and arthropathy were more prevalent in Caucasians than in East Asians (P=9.30×10-3, 1.69×10-2). Among the recurrent mutations, G320V (45 unrelated cases) and L101P (7 unrelated cases) were detected most frequently and restricted to Caucasians. [Q6H; C321*] was predominant in Chinese patients (6 unrelated cases). I281T (Chinese and Greek), A310G (Brazilian and African American), and R385* (Italian and North African) were reported across different ethnicities. In genotype-phenotype correlation analyses, 91.30% of homozygotes with exon 2-3 mutations developed early-onset HH compared to 66.00% of those with exon 4 mutations (P=2.40×10-2). Hypogonadism occurred more frequently in homozygotes with missense mutations (72.55%) than in those with nonsense mutations (35.71%; P=2.43×10-2). Liver biopsy was accepted by more probands with frame-shift or missense mutations (85.71% and 60.78%, respectively) than by those with nonsense mutations (28.57%; P=2.37×10-2, 3.93×10-2). The present review suggests that patients' ethnicity, geographical region, and genetic predisposition should be considered in the diagnosis, prognosis and management of HJV-HH.
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Affiliation(s)
- Xiaomu Kong
- Department of Endocrinology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029 China
| | - Lingding Xie
- Department of Endocrinology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029 China
| | - Haiqing Zhu
- Department of Endocrinology and Metabolism, China Meitan General Hospital, No. 29 Xibahe Nanli, Chaoyang District, Beijing, 100029 China
| | - Lulu Song
- Department of Endocrinology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029 China
| | - Xiaoyan Xing
- Department of Endocrinology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029 China
| | - Wenying Yang
- Department of Endocrinology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029 China
| | - Xiaoping Chen
- Department of Endocrinology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029 China
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Hamdi-Rozé H, Ben Ali Z, Ropert M, Detivaud L, Aggoune S, Simon D, Pelletier G, Deugnier Y, David V, Bardou-Jacquet E. Variable expressivity of HJV related hemochromatosis: "Juvenile" hemochromatosis? Blood Cells Mol Dis 2018; 74:30-33. [PMID: 30389309 DOI: 10.1016/j.bcmd.2018.10.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 10/19/2018] [Accepted: 10/19/2018] [Indexed: 12/18/2022]
Abstract
Juvenile hemochromatosis is a rare autosomal recessive disease due to variants in the Hemojuvelin (HJV) gene. Although biological features mimic HFE hemochromatosis, clinical presentation is worst with massive iron overload diagnosed during childhood. Our study describes clinical features and results of genetic testing for a group of patients initially referred for a hepcidino-deficiency syndrome and for whom HJV hemochromatosis was finally diagnosed. 662 patients with iron overload and high serum transferrin saturation were tested, and five genes (HFE, HJV, HAMP, TFR2, SLC40A1) were sequenced. Among our cohort, ten unrelated patients were diagnosed with HJV hemochromatosis. Genetic testing revealed five previously published and five undescribed variants: p.Arg41Pro, p.His180Arg, p.Lys299Glu, p.Cys361Arg and p.Ala384Val. Surprisingly, this study revealed a late age of onset in some patients, contrasting with the commonly accepted definition of "juvenile" hemochromatosis. Five of our patients were 30 years old or older, including two very late discoveries. Biological features and severity of iron overload were similar in younger and older patients. Our study brings new insight on HJV hemochromatosis showing that mild phenotype and late onset are possible. Genetic testing for HJV variants should thus be performed for all patients displaying a non-p.Cys282Tyr homozygous HFE hemochromatosis with hepcidin deficiency phenotype.
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Affiliation(s)
- Houda Hamdi-Rozé
- Univ Rennes, CHU Rennes, INSERM, French Reference Center for Hemochromatosis and Iron Metabolism Disease, F-35000 Rennes, France; Univ Rennes, CHU Rennes, CNRS, IGDR, UMR 6290, Molecular Genetics Department, F-35000 Rennes, France.
| | - Zeineb Ben Ali
- Univ Rennes, CHU Rennes, INSERM, French Reference Center for Hemochromatosis and Iron Metabolism Disease, F-35000 Rennes, France; Univ Rennes, CHU Rennes, INSERM, Liver Disease Department, F-35000 Rennes, France
| | - Martine Ropert
- Univ Rennes, CHU Rennes, INSERM, French Reference Center for Hemochromatosis and Iron Metabolism Disease, F-35000 Rennes, France; Univ Rennes, CHU Rennes, INSERM, Biochemistry Department, F-35000 Rennes, France
| | - Lénaïck Detivaud
- Univ Rennes, CHU Rennes, INSERM, French Reference Center for Hemochromatosis and Iron Metabolism Disease, F-35000 Rennes, France
| | - Samira Aggoune
- EPH Belfort, Pediatric Department, El Harrach, Alger 16000, Algeria
| | - Dominique Simon
- Hopital Universitaire Robert-Debré, Endocrinology and Pediatric Diabetology, Paris 75019, France
| | - Gilles Pelletier
- Hopital Bicêtre, Hepatogastroenterology, Le Kremlin-Bicêtre 94275, France
| | - Yves Deugnier
- Univ Rennes, CHU Rennes, INSERM, French Reference Center for Hemochromatosis and Iron Metabolism Disease, F-35000 Rennes, France; Univ Rennes, CHU Rennes, INSERM, Liver Disease Department, F-35000 Rennes, France
| | - Véronique David
- Univ Rennes, CHU Rennes, CNRS, IGDR, UMR 6290, Molecular Genetics Department, F-35000 Rennes, France
| | - Edouard Bardou-Jacquet
- Univ Rennes, CHU Rennes, INSERM, French Reference Center for Hemochromatosis and Iron Metabolism Disease, F-35000 Rennes, France; Univ Rennes, CHU Rennes, INSERM, Liver Disease Department, F-35000 Rennes, France
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12
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Lv T, Zhang W, Xu A, Li Y, Zhou D, Zhang B, Li X, Zhao X, Wang Y, Wang X, Duan W, Wang Q, Xu H, Zheng J, Zhao R, Zhu L, Dong Y, Lu L, Chen Y, Long J, Zheng S, Wang W, You H, Jia J, Ou X, Huang J. Non- HFE mutations in haemochromatosis in China: combination of heterozygous mutations involving HJV signal peptide variants. J Med Genet 2018; 55:650-660. [PMID: 30166352 DOI: 10.1136/jmedgenet-2018-105348] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/22/2018] [Accepted: 07/08/2018] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Hereditary haemochromatosis (HH) caused by a homozygous p.C282Y mutation in haemochromatosis (HFE) gene has been well documented. However, less is known about the causative non-HFE mutation. We aimed to assess mutation patterns of haemochromatosis-related genes in Chinese patients with primary iron overload. METHODS Patients were preanalysed for mutations in the classic HH-related genes: HFE, HJV, HAMP, TFR2 and SLC40A1. Whole exome sequencing was conducted for cases with variants in HJV signal peptide region. Representative variants were analysed for biological function. RESULTS None of the cases analysed harboured the HFE p.C282Y; however, 21 of 22 primary iron-overload cases harboured at least one non-synonymous variant in the non-HFE genes. Specifically, p.E3D or p.Q6H variants in the HJV signal peptide region were identified in nine cases (40.9%). In two of three probands with the HJV p.E3D, exome sequencing identified accompanying variants in BMP/SMAD pathway genes, including TMPRSS6 p.T331M and BMP4 p.R269Q, and interestingly, SUGP2 p.R639Q was identified in all the three cases. Pedigree analysis showed a similar pattern of combination of heterozygous mutations in cases with HJV p.E3D or p.Q6H, with SUGP2 p.R639Q or HJV p.C321X being common mutation. In vitro siRNA interference of SUGP2 showed a novel role of downregulating the BMP/SMAD pathway. Site-directed mutagenesis of HJV p.Q6H/p.C321X in cell lines resulted in loss of membrane localisation of mutant HJV, and downregulation of p-SMAD1/5 and HAMP. CONCLUSION Compound heterozygous mutations of HJV or combined heterozygous mutations of BMP/SMAD pathway genes, marked by HJV variants in the signal peptide region, may represent a novel aetiological factor for HH.
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Affiliation(s)
- Tingxia Lv
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Wei Zhang
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Anjian Xu
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yanmeng Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Donghu Zhou
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Bei Zhang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xiaojin Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xinyan Zhao
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yu Wang
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xiaoming Wang
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Weijia Duan
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Qianyi Wang
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Hexiang Xu
- Department of Infectious Diseases, The Third Affiliated Hospital of Anhui Medical University, The First People's Hospital of Hefei, Hefei, China
| | - JiShun Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Anhui Medical University, The First People's Hospital of Hefei, Hefei, China
| | - Rongrong Zhao
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Longdong Zhu
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuwei Dong
- Department of Gastroenterology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lungen Lu
- Department of Gastroenterology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yongpeng Chen
- Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiang Long
- Department of Oncology Minimally Invasive Interventional Radiology, Beijing You-An Hospital, Capital Medical University, Shanghai, China
| | - Sujun Zheng
- Artificial Liver Center, Beijing You-An Hospital, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hong You
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jidong Jia
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xiaojuan Ou
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jian Huang
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China
- Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China
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Ravasi G, Pelucchi S, Mariani R, Silvestri L, Camaschella C, Piperno A. A severe hemojuvelin mutation leading to late onset of HFE2-hemochromatosis. Dig Liver Dis 2018; 50:859-862. [PMID: 29764732 DOI: 10.1016/j.dld.2018.04.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/27/2018] [Accepted: 04/15/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Giulia Ravasi
- University of Milano-Bicocca - Department of Medicine and Surgery, Monza, Italy
| | - Sara Pelucchi
- University of Milano-Bicocca - Department of Medicine and Surgery, Monza, Italy
| | - Raffaella Mariani
- Centre for Rare Diseases - Disorders of Iron Metabolism - ASST-Monza, S. Gerardo Hospital Monza, Italy
| | - Laura Silvestri
- Vita Salute University and Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | - Clara Camaschella
- Vita Salute University and Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | - Alberto Piperno
- University of Milano-Bicocca - Department of Medicine and Surgery, Monza, Italy; Centre for Rare Diseases - Disorders of Iron Metabolism - ASST-Monza, S. Gerardo Hospital Monza, Italy; Medical Genetics - ASST-Monza, S. Gerardo Hospital, Monza, Italy.
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14
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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.
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15
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Laursen AH, Bjerrum OW, Friis-Hansen L, Hansen TO, Marott JL, Magnussen K. Causes of iron overload in blood donors - a clinical study. Vox Sang 2017; 113:110-119. [PMID: 29230833 DOI: 10.1111/vox.12619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 10/31/2017] [Accepted: 11/04/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVES Despite the obligate iron loss from blood donation, some donors present with hyperferritinaemia that can result from a wide range of acute and chronic conditions including hereditary haemochromatosis (HH). The objective of our study was to investigate the causes of hyperferritinaemia in the blood donor population and explore the value of extensive HH mutational analyses. MATERIALS AND METHODS Forty-nine consecutive donors (f = 6, m = 43) were included prospectively from the Capital Regional Blood Center. Inclusion criteria were a single ferritin value >1000 μg/l or repeated hyperferritinaemia with at least one value >500 μg/l. All donors were questioned about their medical history and underwent a physical examination, biochemical investigations and next-generation sequencing of HH-related genes, including the HFE gene, the haemojuvelin gene (HFE2/HJV), the hepcidin gene (HAMP), the ferroportin 1 gene (SLC40A1) and the transferrin receptor 2 gene (TFR2). RESULTS Forty of 49 donors were mutation positive with a combined 69 mutations, 54 of which were located in the HFE gene. There were 11 mutations in the TFR2 gene, two mutations in the HFE2 gene and two mutations in the HAMP gene. Only four donors had apparent alternative causes of hyperferritinaemia. CONCLUSION HH-related mutations were the most frequent cause of hyperferritinaemia in a Danish blood donor population, and it appears that several different HH-genotypes can contribute to hyperferritinaemia. HH screening in blood donors with high ferritin levels could be warranted. HH-related iron overload should not in itself result in donor ineligibility.
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Affiliation(s)
- A H Laursen
- Department of Haematology, Rigshospitalet, Copenhagen, Denmark
| | - O W Bjerrum
- Department of Haematology, Rigshospitalet, Copenhagen, Denmark
| | - L Friis-Hansen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Biochemistry, Nordsjaellands Hospital, Hillerod, Denmark
| | - T O Hansen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark
| | - J L Marott
- The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark
| | - K Magnussen
- Blood Centre Lab, Hvidovre Hospital, Hvidovre, Denmark.,Department of Immunology and Transfusion Medicine, Sorlandet hospital Kristiansand, Kristiansand, Norway
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16
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Kawabata H. The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis. Int J Hematol 2017; 107:31-43. [PMID: 29134618 DOI: 10.1007/s12185-017-2365-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 11/08/2017] [Indexed: 02/06/2023]
Abstract
Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.
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Affiliation(s)
- Hiroshi Kawabata
- Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa-ken, 920-0293, Japan.
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17
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Abstract
Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 µm were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra-structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron.
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18
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Ikuta K, Hatayama M, Addo L, Toki Y, Sasaki K, Tatsumi Y, Hattori A, Kato A, Kato K, Hayashi H, Suzuki T, Kobune M, Tsutsui M, Gotoh A, Aota Y, Matsuura M, Hamada Y, Tokuda T, Komatsu N, Kohgo Y. Iron overload patients with unknown etiology from national survey in Japan. Int J Hematol 2016; 105:353-360. [DOI: 10.1007/s12185-016-2141-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Revised: 11/06/2016] [Accepted: 11/06/2016] [Indexed: 12/21/2022]
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Ogilvie C, Gaffney D, Murray H, Kerry A, Haig C, Spooner R, Fitzsimons EJ. Improved detection of hereditary haemochromatosis. J Clin Pathol 2014; 68:218-21. [PMID: 25540266 DOI: 10.1136/jclinpath-2014-202720] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIMS There is high prevalence of hereditary haemochromatosis (HH) in North European populations, yet the diagnosis is often delayed or missed in primary care. Primary care physicians frequently request serum ferritin (SF) estimation but appear uncertain as how to investigate patients with raised SF values. Our aim was to develop a laboratory algorithm with high predictive value for the diagnosis of HH in patients from primary care with raised SF values. METHODS Transferrin saturation (Tsat) was measured on SF samples sent from primary care; 1657 male and 2077 female patients age ≥ 30 years with SF ≥ 200 μg/L. HFE genotyping was performed on all 878 male and 867 female patients with Tsat >30%. RESULTS This study identified 402 (206 men; 196 women) C282Y carriers and 132 (58 men; 74 women) C282Y homozygotes. Optimal limits for combined SF and Tsat values for HH recognition were established. The detection rate for homozygous C282Y HH for male patients with both SF ≥ 300 μg/L and Tsat >50% was 18.8% (52/272) and 16.3% (68/415) for female patients with both SF ≥ 200 μg/L and Tsat >40%. CONCLUSIONS The large number of SF requests received from primary care should be used as a resource to improve the diagnosis of HH in areas of high prevalence.
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Affiliation(s)
- Catherine Ogilvie
- Department of Haematology, West Glasgow Hospitals University NHS Trust, Glasgow, UK
| | - Dairena Gaffney
- Department of Biochemistry, Glasgow Royal Infirmary, Glasgow, UK
| | - Heather Murray
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
| | - Andrew Kerry
- Department of Clinical Biochemistry, Royal Alexandra Hospital, Paisley, UK
| | - Caroline Haig
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
| | - Richard Spooner
- Department of Biochemistry, Glasgow Royal Infirmary, Glasgow, UK
| | - Edward J Fitzsimons
- Department of Haematology, West Glasgow Hospitals University NHS Trust, Glasgow, UK
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Li S, Xue J, Chen B, Wang Q, Shi M, Xie X, Zhang L. Two middle-age-onset hemochromatosis patients with heterozygous mutations in the hemojuvelin gene in a Chinese family. Int J Hematol 2014; 99:487-92. [DOI: 10.1007/s12185-014-1547-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 02/04/2014] [Accepted: 02/12/2014] [Indexed: 12/21/2022]
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21
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Brissot P, Bardou-Jacquet E, Troadec MB, Mosser A, Island ML, Detivaud L, Loréal O, Jouanolle AM. Molecular diagnosis of genetic iron-overload disorders. Expert Rev Mol Diagn 2014; 10:755-63. [DOI: 10.1586/erm.10.55] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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22
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McDonald CJ, Wallace DF, Crawford DHG, Subramaniam VN. Iron storage disease in Asia-Pacific populations: the importance of non-HFE mutations. J Gastroenterol Hepatol 2013; 28:1087-94. [PMID: 23577916 DOI: 10.1111/jgh.12222] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2013] [Indexed: 01/24/2023]
Abstract
Hereditary hemochromatosis (HH) is a widely recognized and well-studied condition in European populations. This is largely due to the high prevalence of the C282Y mutation of HFE. Although less common than in Europe, HH cases have been reported in the Asia-Pacific region because of mutations in both HFE and non-HFE genes. Mutations in all of the currently known genes implicated in non-HFE HH (hemojuvelin, hepcidin, transferrin receptor 2, and ferroportin) have been reported in patients from the Asia-Pacific region. This review discusses the molecular basis of HH and the genes and mutations known to cause non-HFE HH with particular reference to the Asia-Pacific region. Challenges in the genetic diagnosis of non-HFE HH are also discussed and how new technologies such as next generation sequencing may be informative in the future.
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Affiliation(s)
- Cameron J McDonald
- The Membrane Transport Laboratory, The Queensland Institute of Medical Research, Brisbane, Queensland, Australia
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Hattori A, Miyajima H, Tomosugi N, Tatsumi Y, Hayashi H, Wakusawa S. Clinicopathological study of Japanese patients with genetic iron overload syndromes. Pathol Int 2013; 62:612-8. [PMID: 22924847 DOI: 10.1111/j.1440-1827.2012.02848.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In addition to hemochromatosis, aceruloplasminemia and ferroportin disease may be complicated by iron-induced multiple organ damage. Therefore, clinicopathological features should be evaluated in a wider range of genetic iron disorders. This study included 16 Japanese patients with genetic iron overload syndromes. The responsible genes were CP in four, HAMP in one, HJV in three, TFR2 in five, and SLC40A1 in three patients. No phenotype dissociation was observed in patients with the CP, TFR2, or HAMP genotypes. Two of the three patients with the HJV genotype displayed classic hemochromatosis instead of the juvenile type. Patients with the SLC40A1 genotype were affected by mild iron overload (ferroportin A) or severe iron overload (ferroportin B). Transferrin saturation was unusually low in aceruloplasminemia patients. All patients, except those with ferroportin disease, displayed low serum hepcidin-25 levels. Liver pathology showed phenotype-specific changes; isolated parenchymal iron loading in aceruloplasminemia, periportal fibrosis associated with heavy iron overload in both parenchymal and Kupffer cells of ferroportin B, and parenchyma-dominant iron-loading cirrhosis in hemochromatosis. In contrast, diabetes occurred in all phenotypes of aceruloplasminemia, hemochromatosis, and ferroportin disease B. In conclusion, clinicopathological features were partially characterized in Japanese patients with genetic iron overload syndromes.
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Affiliation(s)
- Ai Hattori
- Department of Medical Technology, Nagoya University Graduate School of Health Sciences, Nagoya, Japan.
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24
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Abstract
INTRODUCTION The discovery of hemochromatosis genes and the availability of molecular-genetic tests considerably modified the knowledge of the disease relative to physiopathology, penetrance, and expression, and had major impact in the diagnostic settings. AREAS COVERED Hemochromatosis is a heterogenous disorder at both genetic and phenotypic level. The review discusses criteria to define patients' iron phenotype and to use molecular tests to diagnose HFE-related and non-HFE hemochromatosis. The material examined includes articles published in the journals covered by PubMed US National Library of Medicine. The author has been working in the field of iron overload diseases for several years and has contributed 18 of the papers cited in the references. EXPERT OPINION Hemochromatosis genotyping is inseparable from phenotype characterization. A full clinical assessment is needed and DNA test performed when data suggest a clear indication of suspicion of being at risk for HH. HFE testing for p.Cys282Tyr mutation and p.His63Asp variant is the first molecular diagnostic step. Genotyping for rare mutations can be offered to patients with negative first-level HFE testing who have iron overload with no other explanation and should be performed in referral centers for iron overload disorders that can provide genetic advice and in-house genotyping services.
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Affiliation(s)
- Alberto Piperno
- University of Milano-Bicocca, Centre for the Diagnosis and Treatment of Hemochromatosis and Iron Disorders, S.Gerardo Hospital, Department of Health Sciences, Monza, Italy.
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25
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Iwayama K, Sugita J, Fukushima K, Ikenouchi H, Suzuki K, Maeda T, Tomoyasu S. [Case report: A case of hereditary hemochromatosis (HH) with left ventricular dysfunction]. NIHON NAIKA GAKKAI ZASSHI. THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE 2012; 101:1069-1071. [PMID: 22730735 DOI: 10.2169/naika.101.1069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Affiliation(s)
- Kosaka Iwayama
- Department of Cardiology, Japanese Red Cross Medical Center, Japan
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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]
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27
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Vantyghem MC, Dobbelaere D, Mention K, Wemeau JL, Saudubray JM, Douillard C. Endocrine manifestations related to inherited metabolic diseases in adults. Orphanet J Rare Dis 2012; 7:11. [PMID: 22284844 PMCID: PMC3349544 DOI: 10.1186/1750-1172-7-11] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2011] [Accepted: 01/28/2012] [Indexed: 02/07/2023] Open
Abstract
Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.
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Affiliation(s)
- Marie-Christine Vantyghem
- Service d'Endocrinologie et Maladies Métaboliques, 1, Rue Polonovski, Hôpital C Huriez, Centre Hospitalier Régional et Universitaire de Lille, 59037 Lille cedex, France.
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Iron disorders of genetic origin: a changing world. Trends Mol Med 2011; 17:707-13. [DOI: 10.1016/j.molmed.2011.07.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 07/13/2011] [Accepted: 07/20/2011] [Indexed: 12/15/2022]
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Maeda T, Nakamaki T, Saito B, Nakashima H, Ariizumi H, Yanagisawa K, Hattori A, Tatsumi Y, Hayashi H, Suzuki K, Tomoyasu S. Hemojuvelin hemochromatosis receiving iron chelation therapy with deferasirox: improvement of liver disease activity, cardiac and hematological function. Eur J Haematol 2011; 87:467-9. [DOI: 10.1111/j.1600-0609.2011.01693.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Kaneko Y, Miyajima H, Piperno A, Tomosugi N, Hayashi H, Morotomi N, Tsuchida KI, Ikeda T, Ishikawa A, Ota Y, Wakusawa S, Yoshioka K, Kono S, Pelucchi S, Hattori A, Tatsumi Y, Okada T, Yamagishi M. Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders. J Gastroenterol 2010; 45:1163-1171. [PMID: 20533066 DOI: 10.1007/s00535-010-0259-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2009] [Accepted: 05/09/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes. METHODS We measured serum iron parameters and hepcidin-25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE hemochromatosis. RESULTS One patient with HJV hemochromatosis, 2 with TFR2 hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. CONCLUSION Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis.
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Affiliation(s)
- Yoshibumi Kaneko
- Department of Internal Medicine, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
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31
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Motonishi S, Hayashi H, Fujita Y, Okada H, Kusakabe A, Ito M, Miyamoto K, Ueno T. Copper- and Iron-rich Matrices in Hepatocellular Lipofuscin Particles of a Young Male Patient: Diagnostic Ultrastructures for Wilson Disease. Ultrastruct Pathol 2009; 30:409-14. [PMID: 17182432 DOI: 10.1080/01913120600854327] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
A 17-year-old male patient appeared with the biochemical liver damage associated with hypoceruloplasminemia and mild iron overload. Genetic analysis identified a compound heterozygosity of ATP7B responsible for the primary copper toxicosis of Wilson disease without mutations in HFE. A liver specimen consisted of cirrhotic nodules of large-sized hepatocytes with fatty change and those of fat-free small-sized hepatocytes. Histochemically, iron was distributed diffusely in the small-sized hepatocytes, while copper grains appeared in a few of the hepatocytes near the fibrous bands. X-ray microanalysis on the liver tissue fixed with a 0.1% osmium tetroxide solution and embedded in epoxy resin disclosed (1) complex formation of copper with sulfur, and iron with phosphorus in the hepatocyte lipofuscin particles, (2) intraparticle localization of the cuprothionein in the less dense matrix and ferric proteins in the dense matrix, and (3) high affinity of the cuprothionein to lead staining. Considering the fact that ceruloplasmin is the major ferroxidase essential for iron efflux, iron deposits in the hypoceruloplasminemic patients with Wilson disease are not a complication, but a natural event. This study disclosed for the first time the diagnostic ultrastructures of Wilson disease, which might represent different detoxification processes to the reactive metals of copper and iron.
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Affiliation(s)
- Satoshi Motonishi
- Department of Pharmacy, University Hospital of Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
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Lee PL, Beutler E. Regulation of hepcidin and iron-overload disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2009; 4:489-515. [PMID: 19400694 DOI: 10.1146/annurev.pathol.4.110807.092205] [Citation(s) in RCA: 133] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hepcidin, a 25-amino-acid antimicrobial peptide, is the central regulator of iron homeostasis. Hepcidin transcription is upregulated by inflammatory cytokines, iron, and bone morphogenetic proteins and is downregulated by iron deficiency, ineffective erythropoiesis, and hypoxia. The iron transporter ferroportin is the cognate receptor of hepcidin and is destroyed as a result of interaction with the peptide. Except for inherited defects of ferroportin and hepcidin itself, all forms of iron-storage disease appear to arise from hepcidin dysregulation. Studies using multiple approaches have begun to delineate the molecular mechanisms that regulate hepcidin expression, particularly at the transcriptional level. Knowledge of the regulation of hepcidin by inflammation, iron, erythropoiesis, and hypoxia will lead to an understanding of the pathogenesis of primary hemochromatosis, secondary iron overload, and anemia of inflammatory disease.
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Affiliation(s)
- Pauline L Lee
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
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33
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Vantyghem MC, Mention C, Dobbelaere D, Douillard C. Hypoglycémies et manifestations endocriniennes des maladies héréditaires du métabolisme chez l’adulte. ANNALES D'ENDOCRINOLOGIE 2009; 70:25-42. [DOI: 10.1016/j.ando.2008.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2008] [Accepted: 12/17/2008] [Indexed: 12/20/2022]
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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.
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Affiliation(s)
- Yasuhiro Nagayoshi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
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Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P. Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. BMC BIOCHEMISTRY 2008; 9:9. [PMID: 18384687 PMCID: PMC2323002 DOI: 10.1186/1471-2091-9-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2007] [Accepted: 04/02/2008] [Indexed: 11/10/2022]
Abstract
BACKGROUND Repulsive guidance molecule c (RGMc or hemojuvelin), a glycosylphosphatidylinositol-linked glycoprotein expressed in liver and striated muscle, plays a central role in systemic iron balance. Inactivating mutations in the RGMc gene cause juvenile hemochromatosis (JH), a rapidly progressing iron storage disorder with severe systemic manifestations. RGMc undergoes complex biosynthetic steps leading to membrane-bound and soluble forms of the protein, including both 50 and 40 kDa single-chain species. RESULTS We now show that pro-protein convertases (PC) are responsible for conversion of 50 kDa RGMc to a 40 kDa protein with a truncated COOH-terminus. Unlike related molecules RGMa and RGMb, RGMc encodes a conserved PC recognition and cleavage site, and JH-associated RGMc frame-shift mutants undergo COOH-terminal cleavage only if this site is present. A cell-impermeable peptide PC inhibitor blocks the appearance of 40 kDa RGMc in extra-cellular fluid, as does an engineered mutation in the conserved PC recognition sequence, while the PC furin cleaves 50 kDa RGMc in vitro into a 40 kDa molecule with an intact NH2-terminus. Iron loading reduces release of RGMc from the cell membrane, and diminishes accumulation of the 40 kDa species in cell culture medium. CONCLUSION Our results define a role for PCs in the maturation of RGMc that may have implications for the physiological actions of this critical iron-regulatory protein.
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Affiliation(s)
- David Kuninger
- Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.
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36
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Hayashi H, Wakusawa S, Yano M, Okada T. Genetic background of Japanese patients with adult-onset storage diseases in the liver. Hepatol Res 2007; 37:777-83. [PMID: 17517077 DOI: 10.1111/j.1872-034x.2007.00114.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In contrast to primary lysosomal diseases in young subjects, adult-onset liver storage disorders may be explained by non-lysosomal genetic defects. The aim of the present review is to summarize the genetic backgrounds of Japanese patients with hemochromatosis of unknown etiology, Wilson disease of primary copper toxicosis, and the black liver of Dubin-Johnson syndrome. Three patients with middle-age onset hemochromatosis were homozygous for mutations of HJV and two patients were homozygous for mutations of TFR2. Minor genes other than HJV and TFR2 might be involved in Japanese patients. Five of the six patients with Wilson disease were compound heterozygous, while the remaining patient was heterozygous for the mutation in ATP7B responsible for copper toxicosis. Involvement of MURR1 was not proved in the heterozygote of ATP7B. Because of ferroxidase deficiency,most patients had secondary lysosomes shared by cuprothioneins and iron complex. Six patients with Dubin-Johnson syndrome were homozygous or compound heterozygous for mutant MRP2. Despite complex metabolic disorders, the syndrome had a single genetic background. Thus, most patients with adult-onset lysosomal proliferation in the liver had genetic defects in non-lysosomal organelles, named the secondary lysosomal diseases. The proliferating lysosomes in these conditions seemed to be heterogeneous in their matrices.
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Affiliation(s)
- Hisao Hayashi
- Department of Medicine, Asanogawa General Hospital, Kanazawa, Japan
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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.
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Affiliation(s)
- Daniel-F Wallace
- Membrane Transport Laboratory, The Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006 Australia
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Abstract
The liver plays a central role in iron metabolism. It is the major storage site for iron and also expresses a complex range of molecules which are involved in iron transport and regulation of iron homeostasis. An increasing number of genes associated with hepatic iron transport or regulation have been identified. These include transferrin receptors (TFR1 and 2), a ferrireductase (STEAP3), the transporters divalent metal transporter-1 (DMT1) and ferroportin (FPN) as well as the haemochromatosis protein, HFE and haemojuvelin (HJV), which are signalling molecules. Many of these genes also participate in iron regulatory pathways which focus on the hepatic peptide hepcidin. However, we are still only beginning to understand the complex interactions between liver iron transport and iron homeostasis. This review outlines our current knowledge of molecules of iron metabolism and their roles in iron transport and regulation of iron homeostasis.
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Affiliation(s)
- Ross-M Graham
- School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, PO Box 480, Fremantle 6959, Western Australia, Australia
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Abstract
BACKGROUND Since the seminal discovery of the HFE gene a decade ago, considerable further progress in unravelling the genetic basis of haemochromatosis has been made. Novel genes and iron overload phenotypes have been described with potential insights into the molecular pathophysiology of human iron metabolism. AIM To review recent key advances in the field of inherited iron overload and assess their impact on clinical practice and on our understanding of iron regulation. METHODS A PubMed search was undertaken predominantly using 'haemochromatosis', 'HFE', 'hepcidin' and 'ferroportin'. Illustrative cases were sought. RESULTS The impact of HFE mutation analysis on the management of haemochromatosis is significant and allows early accurate diagnosis. HFE is also implicated in the siderosis associated with other liver pathologies. Non-HFE genes underpinning other forms of haemochromatosis are now recognized and genotype-phenotype interactions result in a spectrum of disease. These novel gene products interact with HFE in a common pathway for iron homeostasis. CONCLUSIONS Further identification of non-HFE genes associated with iron homeostasis will enhance our diagnostic certainty of primary haemochromatosis and may explain the variable expression seen in HFE-related disease. Improving our understanding of the mechanisms of iron regulation may lead to novel therapeutic strategies for the management of iron overload.
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Affiliation(s)
- W J H Griffiths
- Department of Hepatology, Cambridge University Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge, UK.
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Fujita N, Sugimoto R, Takeo M, Urawa N, Mifuji R, Tanaka H, Kobayashi Y, Iwasa M, Watanabe S, Adachi Y, Kaito M. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007; 13:97-104. [PMID: 17515961 PMCID: PMC1869620 DOI: 10.2119/2006-00057.fujita] [Citation(s) in RCA: 156] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2006] [Accepted: 11/13/2006] [Indexed: 12/16/2022] Open
Abstract
Patients with chronic hepatitis C frequently have serum and hepatic iron overload, but the mechanism is unknown. Recently identified hepcidin, exclusively synthesized in the liver, is thought to be a key regulator for iron homeostasis and is induced by infection and inflammation. This study was conducted to determine the hepatic hepcidin expression levels in patients with various liver diseases. We investigated hepcidin mRNA levels of liver samples by real-time detection-polymerase chain reaction; 56 were hepatitis C virus (HCV) positive, 34 were hepatitis B virus (HBV) positive, and 42 were negative for HCV and HBV (3 cases of auto-immune hepatitis, 7 alcoholic liver disease, 13 primary biliary cirrhosis, 9 nonalcoholic fatty liver disease, and 10 normal liver). We analyzed the relation of hepcidin to clinical, hematological, histological, and etiological findings. Hepcidin expression levels were strongly correlated with serum ferritin (P < 0.0001) and the degree of iron deposit in liver tissues (P < 0.0001). Hepcidin was also correlated with hematological parameters (vs. hemoglobin, P = 0.0073; vs. serum iron, P = 0.0012; vs. transferrin saturation, P < 0.0001) and transaminase levels (P = 0.0013). The hepcidin-to-ferritin ratio was significantly lower in HCV(+) patients than in HBV(+) patients (P = 0.0129) or control subjects (P = 0.0080). In conclusion, hepcidin expression levels in chronic liver diseases were strongly correlated with either the serum ferritin concentration or degree of iron deposits in the liver. When adjusted by either serum ferritin values or hepatic iron scores, hepcidin indices were significantly lower in HCV(+) patients than in HBV(+) patients, suggesting that hepcidin may play a pivotal role in the pathogenesis of iron overload in patients with chronic hepatitis C.
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Affiliation(s)
- Naoki Fujita
- Department of Gastroenterology and Hepatology, Division of Clinical Medicine and Biomedical Science, Institute of Medical Science, Mie University Graduate School of Medicine, Mie, Japan.
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Silvestri L, Pagani A, Fazi C, Gerardi G, Levi S, Arosio P, Camaschella C. Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood 2007; 109:4503-10. [PMID: 17264300 DOI: 10.1182/blood-2006-08-041004] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Hemojuvelin (HJV) positively modulates the iron regulator hepcidin, and its mutations are the major cause of juvenile hemochromatosis (JH), a recessive disease leading to iron overload. Defective HJV reduces hepcidin up-regulation both in humans and in Hjv-deficient mice. To investigate the JH pathogenesis and the functional properties of human HJV we studied the biosynthesis and maturation of 6 HJV pathogenic mutants in HeLa and HepG2 cells. We show that proteolytic processing is defective in mutants F170S, W191C, and G320V, but not in G99V and C119F. Moreover, we show that mutants G99V and C119F are targeted to the cell surface, while F170S, W191C, G320V, and R326X (lacking the glycosilphosphatidylinositol [GPI] anchor) are mainly retained in the endoplasmic reticulum, although all mutants are released as soluble forms (s-HJV) in a proportion that is modulated by iron supplementation. Membrane HJV (m-HJV) is mainly composed of the cleaved protein, and its level is increased by iron in wild-type (WT) mice but not in the mutants. Altogether, the data demonstrate that the loss of HJV membrane export is central to the pathogenesis of JH, and that HJV cleavage is essential for the export. The results support a dual function for s- and m-HJV in iron deficiency and overload, respectively.
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Hayashi H, Yano M, Fujita Y, Wakusawa S. Compound overload of copper and iron in patients with Wilson's disease. Med Mol Morphol 2006; 39:121-6. [PMID: 16998622 DOI: 10.1007/s00795-006-0326-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2006] [Accepted: 06/01/2006] [Indexed: 12/12/2022]
Abstract
This review of the copper-iron interaction in Wilson's disease was mainly based on ten patients (three females and seven males) studied in our institutes because the genetic tests of ATP7B for Wilson's disease of primary copper toxicosis and HFE for hemochromatosis, the biochemical parameters of copper and iron, and morphological studies on biopsied liver specimens were complete. All patients had hypoceruloplasminemia and hepatic lesions compatible with Wilson's disease. One patient was homozygous and nine patients were compound heterozygous for the mutations in ATP7B, and all patients were free from the major mutation, C282Y, of HFE. The biochemical parameters of iron metabolism were not specific, except for serum ferritin concentration. Judging from the traditional criteria, seven patients had hyperferritinemia. Histochemical iron was stained in the livers of seven patients and histochemical copper was found in nine patients. Microanalysis was more sensitive than histochemistry, detecting copper and iron accumulation in the hepatocellular lipofuscin particles of all patients. Using an improved fixative, intralipofuscin distribution was found to be different between cuprothionein and iron complexes. Iron overload in Wilson's disease might be worsened after treatment because of the close relation to hypoceruloplasminemia, in which the iron efflux from the liver to the circulation is disturbed.
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Affiliation(s)
- Hisao Hayashi
- Department of Medicine, Asanogawa General Hospital, Kanazawa, Japan.
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Pietrangelo A, Corradini E, Ferrara F, Vegetti A, De Jong G, Luca Abbati G, Paolo Arcuri P, Martinelli S, Cerofolini E. Magnetic resonance imaging to identify classic and nonclassic forms of ferroportin disease. Blood Cells Mol Dis 2006; 37:192-196. [PMID: 17052926 DOI: 10.1016/j.bcmd.2006.08.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2006] [Revised: 08/30/2006] [Accepted: 08/30/2006] [Indexed: 12/25/2022]
Abstract
The ferroportin-related disorder is an increasingly recognized cause of hereditary iron overload. Based on the in vitro behavior of different ferroportin mutant subsets, it was suggested that different forms of the disorder might exist in humans. We used MRI to address this question in vivo in 22 patients from four different pedigrees carrying different ferroportin mutations: A77D, N144H, G80S and Val 162del. We found that, based on the iron status of spleen and bone macrophages, two different forms of the disease can be identified: a classic, common form, characterized by hepatocyte, splenic macrophage and bone marrow macrophage iron retention in patients carrying the A77D, G80S and Val 162del ferroportin variants; a rarer non-classic form, associated with liver iron overload but normal spleen and bone marrow iron content in patients with the N144H mutation. The two forms are likely caused by lack- or gain-of-protein function, respectively. Interestingly, in treated patients with the classic form, the spleen and the spine show appreciable iron accumulation even when serum ferritin is normal and liver iron content low. In conclusion, MRI is a useful non-invasive diagnostic tool to categorize and diagnose the disorder, monitor the status of iron depletion and gain insights on its natural history and management.
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Affiliation(s)
- Antonello Pietrangelo
- Center for Hemochromatosis, Department of Internal Medicine, University Hospital of Modena and Reggio Emilia, Policlinico, Via del Pozzo 71 41100 Modena, Italy.
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Abstract
PURPOSE OF REVIEW Publications concerning liver histopathology in fatty liver disease and chronic hepatitis C, iron and copper overload, and liver transplantation from the past year have been surveyed to highlight useful concepts and diagnostic information. RECENT FINDINGS Two microscopic forms of pediatric nonalcoholic steatohepatitis have been described: type 1 in which hepatocyte ballooning and/or pericellular fibrosis accompany the steatosis; and type 2 which has portal tract inflammation and/or fibrosis as the salient accompanying feature. In chronic hepatitis C, the ductular reaction appears to be a major factor associated with fibrosis. In patients transplanted for hepatitis C virus-related cirrhosis, immunostaining of post-transplant liver biopsies for alpha-smooth muscle actin (i.e. in activated hepatic stellate cells) may identify those individuals at risk for severe recurrence. Clinicopathological papers on several forms of non-HFE hemochromatosis were published and Wilson's disease was described in individuals of 60 years or more in age. Cholestasis in childhood was expertly reviewed and histopathologic precursor lesions of hepatocellular carcinoma were also examined in a comprehensive article. SUMMARY Recent publications with impact on liver biopsy interpretation include a morphologic classification of nonalcoholic steatohepatitis in childhood, the differential diagnosis of childhood cholestasis and pathogenetic factors involved in fibrogenesis in chronic hepatitis C.
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Affiliation(s)
- Jay H Lefkowitch
- Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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45
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Hayashi H, Wakusawa S, Motonishi S, Miyamoto KI, Okada H, Inagaki Y, Ikeda T. Genetic background of primary iron overload syndromes in Japan. Intern Med 2006; 45:1107-11. [PMID: 17106152 DOI: 10.2169/internalmedicine.45.1876] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The different prevalences of iron overload syndromes between Caucasians and Asians may be accounted for by the differences in genetic background. The major mutation of hemochromatosis in Celtic ancestry, C282Y of HFE, was reported in a Japanese patient. Five patients of 3 families with the hepatic transferrin receptor gene (TFR2)-linked hemochromatosis were found in different areas of Japan, suggesting that TFR2 is a major gene in Japanese people. Three patients with mutations in the hemojuvelin gene, HJV, showed also middle-age-onset hemochromatosis. A heterozygous mutation in the H ferritin gene, FTH1, was found in a family of 3 affected patients. Another autosomal dominant SLC40A1-linked hyperferritinemia (ferroportin disease) was found in 3 patients of 2 families. Two patients with hemochromatosis were free from any mutations in the genes investigated. In conclusion, the genetic backgrounds of Japanese patients with primary iron overload syndromes were partially clarified, showing some phenotype-genotype correlations.
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Affiliation(s)
- Hisao Hayashi
- Department of Medicine, Aichi Gakuin University School of Pharmacy, Nagoya
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