A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis

Ot, Njajou; Vaessen, Norbert; Joosse, Marijke; Berghuis, Bianca; Jw, van Dongen; Mh, Breuning; Pj, Snijders; Wp, Rutten; La, Sandkuijl; Ba, Oostra; Duijn, van; Heutink, Peter

doi:10.1038/90038

Cited by 450 publications

(239 citation statements)

References 13 publications

Supporting

Mentioning

221

Contrasting

Unclassified

Order By: Relevance

“…The median ferritin level for the whole group was 861.5 μg/L (range 17-10,000), and the median quantity of iron removed by phlebotomy was 4.25 g (range 0. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The iron removed was ≥5 g in 43 patients.…”

Section: Resultsmentioning

confidence: 99%

“…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]. Some authors have described mutations in HAMP and HJV as genetic modifiers of the hemochromatosis phenotype in humans [10,12,15].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…23,24,25 Patients with a major form of ferroportin disease (type A) present with macrophage iron deposition and high ferritin levels despite normal transferrin saturation. 21,22 In contrast, patients with the minor form (type B) develop abnormalities, such as elevated transferrin saturation and a more severe, mixed iron overload in parenchymal and reticuloendothelial cells similar to typical hemochromatosis. 23,26 It is interesting that the urinary output of hepcidin increases in type A 27 and is normal in type B ferroportin disease.…”

Section: Introductionmentioning

confidence: 99%

“…The disease is inherited as an autosomal dominant trait, 21,22 and occurs in populations throughout the world. 23,24,25 Patients with a major form of ferroportin disease (type A) present with macrophage iron deposition and high ferritin levels despite normal transferrin saturation.…”

Section: Introductionmentioning

confidence: 99%

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

et al. 2010

View full text Add to dashboard Cite

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. (231 words)

show abstract

“…The transferrin/transferrin receptor system is responsible for the regulated delivery of iron to most vertebrate cells (2). In the past decade, other crucial iron-regulatory genes including HFE (encoding HFE) (3), TfR2 (encoding transferrin receptor 2) (4), SLC40A1 (encoding ferroportin) (5)(6)(7)(8), HAMP (encoding hepcidin) (9)(10)(11), and HFE2 (encoding hemojuvelin or HJV) 1 (12) have been discovered, and studies of their physiological roles have revealed additional aspects of mammalian iron homeostasis. Mutations in these genes cause hereditary hemochromatosis (HH), characterized by excess absorption and storage of iron in tissues and organs, eventually leading to irreversible organ damage (13).…”

mentioning

confidence: 99%

Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains

et al. 2008

View full text Add to dashboard Cite

Hemojuvelin is a recently identified iron-regulatory protein that plays an important role in affecting the expression of hepcidin, a key iron regulatory hormone. Although the underlying mechanism of this process is not clear, several hemojuvelin-binding proteins, including the cell surface receptor neogenin and bone morphogenetic protein (BMP) cytokines, have been identified. The ectodomain of neogenin is composed of four immunoglobulin-like (Ig) domains followed by six fibronectin type III-like (FNIII) domains. Here we report expression of soluble versions of hemojuvelin and neogenin for biochemical characterization of their interaction and the interaction of HJV with BMP-2. Hemojuvelin normally undergoes an autocatalytic cleavage, and as in ViVo, recombinant hemojuvelin exists as a mixture of cleaved and uncleaved forms. Neogenin binds to cleaved and noncleaved hemojuvelin, as verified by its binding to an uncleaved mutant hemojuvelin. We localized the hemojuvelin binding site on neogenin to the membrane-proximal fifth and sixth FNIII domains and the juxtamembrane linker and showed that a fragment containing only this region binds 2-3 orders of magnitude more tightly than the entire neogenin ectodomain. Binding to the most membrane-proximal region of neogenin may play a role in regulating the levels of soluble and membrane-bound forms of hemojuvelin, which in turn would influence the amount of free BMP-2 available for binding to its receptors and triggering transcription of the hepcidin gene. Our finding that BMP-2 and neogenin bind simultaneously to hemojuvelin raises the possibility that neogenin is part of a multiprotein complex at the hepatocyte membrane involving BMP, its receptors, and hemojuvelin.

show abstract

A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis

Cited by 450 publications

References 13 publications

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

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

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

Neogenin Interacts with Hemojuvelin through Its Two Membrane-Proximal Fibronectin Type III Domains

Contact Info

Product

Resources

About