Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis

Merryweather‐Clarke, Alison T.; Cadet, Estelle; Bomford, Adrian; Capron, Dominique; Viprakasit, Vip; Miller, A.L.C.; McHugh, Peter J.; Chapman, Roger W.; Pointon, Jennifer J.; Wimhurst, Victoria L. C.; Livesey, K; Tanphaichitr, Voravarn S.; Rochette, Jacques; Robson, Kathryn

doi:10.1093/hmg/ddg225

Cited by 236 publications

(160 citation statements)

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“…Only in the case of hepcidin mutations is there some evidence of modification of the expression of the C282Y homozygous state. Co-inheritance of hepcidin mutations appears to increase iron loading in homozygotes for the C282Y mutation [60,66,68]. Such hepcidin mutations are excessively rare; we have never encountered one in our sizeable experience.…”

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confidence: 80%

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Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves.Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it became to be considered the most common disease of Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and it is only the genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype.Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias.While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.It is a great honor for me to present this lecture in memory of my good friend Bracha Ramot. It is because this lecture is in honor of Bracha that I do not feel the least bit uncomfortable speaking about iron storage diseases in a symposium entitled "Genomics and Molecular Biology of Hematopoietic Malignancies". I know that had it been possible to ask her whether this might be appropriate Bracha would have said: "Of course, Ernie. Talk about whatever you want to". That was her way. And, of course, Bracha was no stranger to iron metabolism. She was scientifically broad, a Renaissance hematologist. A MEDLINE search reveals 261 publications by Bracha and eight of those deal with iron --iron in thalassemia, iron in sideroblastic anemia, and iron in iron deficiency anemia.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable...

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confidence: 80%

“…Considerable effort has been expended, particularly by our laboratory [52][53][54][55][56][57][58] but also by others [59][60][61][62][63][64][65][66][67] to find mutations that interact with HFE mutations to increase or decrease the penetrance. These efforts have been virtually entirely fruitless.…”

Section: Genetic Modifiers Of Hereditary Hemochromatosismentioning

confidence: 99%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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“…35 (v) Our study does not take into account potential differences in the penetrance of variants or the possibility that iron overload can be caused by digenic inheritance of variants in HFE and other non-HFE genes. 36 For example, the p.His63Asp and p.Ser65Cys variants in HFE are known to contribute to some cases of iron overload but have a much lower penetrance than p.Cys282Tyr. 7,8 We decided to exclude these variants from our analysis so as not to over inflate population prevalence estimates.…”

Section: Discussionmentioning

confidence: 99%

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

Wallace

Subramaniam

2016

Genetics in Medicine

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Purpose:The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH.Methods: A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined.Results: Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. Conclusion:We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.

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“…Purified PCR products presenting altered profiles were directly sequenced using the ABI Prism BigDye Terminator v1.1 Cycle Sequencing Kit in the ABI Prism 3130xl Genetic Analyzer (Applied Biosystems). Codifying regions of HJV and HAMP genes were screened by dHPLC as described or were directly sequenced [18,19,27,29].…”

Section: Molecular Studiesmentioning

confidence: 99%

“…Other very rare or private HFE variants have been reported in affected individuals, contributing to the HH genetic heterogeneity [3][4][5][6][7][8][9][10]. Moreover, an association of HH with other genes, such as the transferrin receptor 2 (TFR2) [11][12][13][14][15][16], the hemojuvelin (HJV) [17][18][19][20][21][22][23][24][25] and the hepcidin (HAMP) [14,[26][27][28][29][30][31] genes, has also been documented. These latter two genes are mainly associated with the juvenile form of the disease (Juvenile Hemochromatosis, JH).…”

Section: Introductionmentioning

confidence: 99%