Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis

Roetto, Antonella; Papanikolaou, George; Politou, Marianna; Alberti, Federica; Girelli, Domenico; Christakis, John; Loukopoulos, Dimitris; Camaschella, Clara

doi:10.1038/ng1053

Cited by 776 publications

(521 citation statements)

References 15 publications

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“…Most studies confirming the role of hepcidin in iron metabolism have been performed in experimental animals. Institution of an iron-free diet, production of the anemic state, and hypoxia are associated with decreased hepcidin production, while increased hepcidin production is noted in acute inflammation [16,17]. The discrepancy between these two disorders with respect to the serum hepcidin in patients with renal failure, in which elevated hepcidin levels were observed, may in part reflect an underlying inflammatory state associated with advanced renal failure, loss of kidney function, and development of anemia of chronic disease.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis

Małyszko

Pawlak

et al. 2006

Am. J. Hematol.

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Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. Hepcidin could also act as an indicator of functional iron deficiency in these patients. Cross-sectional study was performed to assess hepcidin correlations with renal function, iron status, and hsCRP in patients with chronic renal failure on conservative treatment, on hemodialyses, and in kidney transplant recipients. Iron status, complete blood count, creatinine, albumin, lipids were assessed using standard laboratory methods. GFR was estimated using MDRD formula. Hepcidin and high sensitivity CRP were measured using commercially available kits. Ferritin and hepcidin were higher in hemodialyzed patients, kidney transplant recipients, and patients with chronic renal failure over controls. In patients with chronic renal failure, hepcidin correlated significantly with total protein, albumin, creatinine, and eGRF. In kidney transplant recipients, hepcidin correlated significantly in univariate analysis, with total protein, ferritin, time after transplantation, creatinine, eGRF and tended to correlate with cholesterol. In hemodialyzed patients hepcidin, correlated significantly with triglycerides, albumin, creatinine, urea, residual renal function, and hsCRP. In healthy volunteers, hepcidin was related to triglycerides and ferritin. Multiple regression analysis in hemodialyzed patients showed that hepcidin was independently related to creatinine, triglycerides, and residual renal function. Multiple regression analysis in kidney transplant recipients showed that hepcidin was independently related only to GFR and ferritin. Elevated hepcidin in all groups of patients studied may be due to low grade inflammation, frequently encountered in this population and mainly to impaired renal function. Am. J. Hematol. 81:832-837, 2006. V V C 2006 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis

Małyszko

Pawlak

et al. 2006

Am. J. Hematol.

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“…Other forms of hemochromatosis include type 2 or juvenile hemochromatosis, which can be caused by mutations in the HAMP, the gene coding for the iron regulatory peptide hepcidin [21] or in the hemojuvelin gene [18]. Type 3 is caused by mutations in the transferrin receptor 2 gene [8], and type 4 is described as an autosomal dominant iron overload that develops from a pathogenic mutation in the SLC40a1 gene (ferroportin disease) [16,17,20].…”

Section: Introductionmentioning

confidence: 99%

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene

Altés

Bach²,

Ruiz³

et al. 2009

Ann Hematol

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Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

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“…The consequence is an over expression of DMT1, which in turn is responsible for enhanced iron absorption in villous cells of the small intestine [9,32]. However, this pathogenic model of HFE-related hereditary hemochromatosis, also called crypt-programming model, has been challenged after the discovery of hepcidin, a peptide that has a key role in human iron metabolism and which is associated with juvenile hereditary hemochromatosis [9,[34][35][36]. Hepcidin is a newly described protein in iron transport which was isolated by Park and colleagues [37] and derives the name from its origin in the liver (hep-) and its antimicrobial properties in vitro (-cidin).…”

Section: Type 1 Hereditary Hemochromatosis (Omim 235200)mentioning

confidence: 99%

Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment

Franchini

2006

Am. J. Hematol.

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Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated timely. The elucidation of the molecular pathways of iron transport through cells and its control has led to the understanding of various genetic iron‐loading conditions. Four types of inherited iron overload have been recognized: type 1, the most common form with an autosomal recessive inheritance, is associated with mutations in the HFE gene on chromosome 6; type 2 (juvenile hemochromatosis) is an autosomal recessive disorder with causative mutations identified in the HJV gene (subtype A) on chromosome 1 and the HAMP gene (subtype B) on chromosome 19; type 3 has also an autosomal recessive inheritance with mutations in the TfR2 gene on chromosome 3; type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene on chromosome 2. In this review, the genetics, pathophysiology, diagnosis, clinical features, and management of these different types of hereditary hemochromatosis are briefly discussed. Am. J. Hematol. 81:202–209, 2006. © 2006 Wiley‐Liss, Inc.

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Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis

Cited by 776 publications

References 15 publications

Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis

Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene

Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment

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