Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-669899f699-7tmb6 Total loading time: 0 Render date: 2025-04-28T10:34:05.756Z Has data issue: false hasContentIssue false

12 - Hemochromatosis associated with ferroportin gene (SLC40A1) mutations

Published online by Cambridge University Press:  01 June 2011

James C. Barton ,
Corwin Q. Edwards ,
Pradyumna D. Phatak ,
Robert S. Britton  and
Bruce R. Bacon
By
James C. Barton ,
Corwin Q. Edwards ,
Pradyumna D. Phatak ,
Robert S. Britton  and
Bruce R. Bacon
James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah Medical Center
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah School of Medicine, Salt Lake City
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
Get access

Summary

Mutations in the SLC40A1 (FPN1) gene that encodes ferroportin (OMIM *604653) cause an uncommon, heterogeneous group of iron overload disorders characterized by an autosomal dominant pattern of inheritance (OMIM #606069). Ferroportin hemochromatosis has been described worldwide in a variety of race/ethnicity groups. SLC40A1 mutations cause two major iron overload phenotype patterns, each depending on the particular mutation and its effect on the function of the transcribed ferroportin protein. In many ferroportin hemochromatosis kinships, serum iron measures and complications of iron overload typical of other types of hemochromatosis are relatively uncommon. The collective term “ferroportin disease” or “hemochromatosis type 4” is sometimes used to describe the clinical manifestations of ferroportin mutations.

History

In 1990, an autosomal dominant form of hemochromatosis was reported in a Melanesian pedigree from the Solomon Islands. All affected individuals had serum iron measures and a pattern of liver iron staining similar to those of HFE hemochromatosis, although linkage of this disorder to chromosome 6p was excluded. In 1999, Pietrangelo and colleagues reported a large Italian family that included persons with an iron overload condition that occurred in pattern consistent with autosomal dominant inheritance. Based on microsatellite marker analyses, this disorder was also not linked to chromosome 6p. In 2001, Njajou and colleagues identified the SLC40A1 mutation N144H associated with autosomal dominant hemochromatosis in a large multi-generation family from the Netherlands.

Type
Chapter
Information
Handbook of Iron Overload Disorders , pp. 171 - 180
Publisher: Cambridge University Press
Print publication year: 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Eason, RJ, Adams, PC, Aston, CE, Searle, J. Familial iron overload with possible autosomal dominant inheritance. Aust N Z J Med 1990; 20: 226–30.CrossRefGoogle ScholarPubMed
Pietrangelo, A, Montosi, G, Totaro, A, et al. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 1999; 341: 725–32.CrossRefGoogle ScholarPubMed
Njajou, OT, Vaessen, N, Joosse, M, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 2001; 28: 213–14.CrossRefGoogle ScholarPubMed
Montosi, G, Donovan, A, Totaro, A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001; 108: 619–23.CrossRefGoogle ScholarPubMed
Arden, KE, Wallace, DF, Dixon, JL, et al. A novel mutation in ferroportin 1 is associated with haemochromatosis in a Solomon Islands patient. Gut 2003; 52: 1215–17.CrossRefGoogle Scholar
Njajou, OT, Jong, G, Berghuis, B, et al. Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics. Blood Cells Mol Dis 2002; 29: 439–43.CrossRefGoogle ScholarPubMed
Sham, RL, Phatak, PD, West, C, Lee, P, Andrews, C, Beutler, E. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. Blood Cells Mol Dis 2005; 34: 157–61.CrossRefGoogle ScholarPubMed
Cazzola, M, Cremonesi, L, Papaioannou, M, et al. Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3). Br J Haematol 2002; 119: 539–46.CrossRefGoogle Scholar
Devalia, V, Carter, K, Walker, AP, et al. Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 2002; 100: 695.CrossRefGoogle Scholar
Roetto, A, Merryweather-Clarke, AT, Daraio, F, et al. A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4. Blood 2002; 100: 733–4.CrossRefGoogle ScholarPubMed
Wallace, DF, Pedersen, P, Dixon, JL, et al. Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 2002; 100: 692–4.CrossRefGoogle ScholarPubMed
Wallace, DF, Browett, P, Wong, P, Kua, H, Ameratunga, R, Subramaniam, VN. Identification of ferroportin disease in the Indian subcontinent. Gut 2005; 54: 567–8.CrossRefGoogle ScholarPubMed
Zoller, H, McFarlane, I, Theurl, I, et al. Primary iron overload with inappropriate hepcidin expression in V162del ferroportin disease. Hepatology 2005; 42: 4662.CrossRefGoogle ScholarPubMed
Wallace, DF, Subramaniam, VN. Non-HFE haemochromatosis. World J Gastroenterol 2007; 13: 4690–8.CrossRefGoogle ScholarPubMed
Subramaniam, VN, Wallace, DF, Dixon, JL, Fletcher, LM, Crawford, DHG. Ferroportin disease due to the A77D mutation in Australia. Gut 2005; 54: 1048–9.CrossRefGoogle ScholarPubMed
Agarwal, S, Sankar, VH, Tewari, D, Pradhan, M. Ferroportin (SLC40A1) gene in thalassemic patients of Indian descent. Clin Genet 2006; 70: 86.CrossRefGoogle ScholarPubMed
Barton, JC, Acton, RT, Rivers, CA, et al. Genotypic and phenotypic heterogeneity of African-Americans with primary iron overload. Blood Cells Mol Dis 2003; 31: 310–19.CrossRefGoogle ScholarPubMed
Beutler, E, Barton, JC, Felitti, VJ, et al. Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis 2003; 31: 305–9.CrossRefGoogle ScholarPubMed
Gordeuk, VR, Caleffi, A, Corradini, E, et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis 2003; 31: 299–304.CrossRefGoogle Scholar
Barton, JC, Acton, RT, Lee, PL, West, C.SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent. Blood Cells Mol Dis 2007; 39: 206–11.CrossRefGoogle ScholarPubMed
Rivers, CA, Barton, JC, Gordeuk, VR, et al. Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African-Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Blood Cells Mol Dis 2007; 38: 2472.CrossRefGoogle ScholarPubMed
Nemeth, E, Tuttle, MS, Powelson, J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090–3.CrossRefGoogle ScholarPubMed
Donovan, A, Brownlie, A, Zhou, Y, et al. Positional cloning of zebrafish ferroportin 1 identifies a conserved vertebrate iron exporter. Nature 2000; 403: 776–81.CrossRefGoogle ScholarPubMed
Donovan, A, Lima, CA, Pinkus, JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1: 191–200.CrossRefGoogle ScholarPubMed
McKie, AT, Marciani, P, Rolfs, A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000; 5: 299–309.CrossRefGoogle ScholarPubMed
Domenico, I, Nemeth, E, Nelson, JM, et al. The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab 2008; 8: 1466.CrossRefGoogle ScholarPubMed
Domenico, I, Lo, E, Ward, DM, Kaplan, J. Hepcidin-induced internalization of ferroportin requires binding and co-operative interaction with Jak2. Proc Natl Acad Sci USA 2009; 106: 3800.CrossRefGoogle Scholar
Domenico, I, Ward, DM, Nemeth, E, et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci USA 2005; 102: 8955–60.CrossRefGoogle ScholarPubMed
Andrews, NC. Of mice and iron: ferroportin disease. Blood 2007; 109: 4115.CrossRefGoogle Scholar
Zohn, IE, Domenico, I, Pollock, A, et al. The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 2007; 109: 4174–80.CrossRefGoogle ScholarPubMed
Domenico, I, Ward, DM, Musci, G, Kaplan, J. Iron overload due to mutations in ferroportin. Haematologica 2006; 91: 92.Google ScholarPubMed
Sham, RL, Phatak, PD, Nemeth, E, Ganz, T. Hereditary hemochromatosis due to resistance to hepcidin: high hepcidin concentrations in a family with C326S ferroportin mutation. Blood 2009; 114: 493–4.CrossRefGoogle Scholar
Fernandes, A, Preza, GC, Phung, Y, et al. The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood 2009; 114: 437–43.CrossRefGoogle ScholarPubMed
Aisen, P, Enns, C, Wessling-Resnick, M. Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 2001; 33: 9409.CrossRefGoogle ScholarPubMed
Syed, BA, Beaumont, NJ, Patel, A, et al. Analysis of the human hephaestin gene and protein: comparative modeling of the N-terminus ecto-domain based upon ceruloplasmin. Protein Eng 2002; 15: 205–14.CrossRefGoogle Scholar
Pietrangelo, A. The ferroportin disease. Blood Cells Mol Dis 2004; 32: 131–8.CrossRefGoogle ScholarPubMed
Corradini, E, Ferrara, F, Pollicino, T, et al. Disease progression and liver cancer in the ferroportin disease. Gut 2007; 56: 1030–2.CrossRefGoogle ScholarPubMed
Pietrangelo, A, Corradini, E, Ferrara, F, et al. Magnetic resonance imaging to identify classic and non-classic forms of ferroportin disease. Blood Cells Mol Dis 2006; 37: 192–6.CrossRefGoogle ScholarPubMed
Drakesmith, H, Schimanski, LM, Ormerod, E, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 2005; 106: 1092.CrossRefGoogle ScholarPubMed
Cunat, S, Giansily-Blaizot, M, Bismuth, M, et al. Global sequencing approach for characterizing the molecular background of hereditary iron disorders. Clin Chem 2007; 53: 2060–9.CrossRefGoogle ScholarPubMed
Liu, W, Shimomura, S, Imanishi, H, et al. Hemochromatosis with mutation of the ferroportin 1 (IREG1) gene. Intern Med 2005; 44: 285–9.CrossRefGoogle ScholarPubMed
Koyama, C, Wakusawa, S, Hayashi, H, et al. A Japanese family with ferroportin disease caused by a novel mutation of SLC40A1 gene: hyperferritinemia associated with a relatively low transferrin saturation of iron. Intern Med 2005; 44: 990–3.CrossRefGoogle Scholar
Pelucchi, S, Mariani, R, Salvioni, A, et al. Novel mutations of the ferroportin gene (SLC40A1): analysis of 56 consecutive patients with unexplained iron overload. Clin Genet 2008; 73: 171–8.CrossRefGoogle ScholarPubMed
Corradini, E, Montosi, G, Ferrara, F, et al. Lack of enterocyte iron accumulation in the ferroportin disease. Blood Cells Mol Dis 2005;35: 315–18.CrossRefGoogle ScholarPubMed
Domenico, I, McVey, WD, Nemeth, E, et al. Molecular and clinical correlates in iron overload associated with mutations in ferroportin. Haematologica 2006; 91: 1092.Google ScholarPubMed
Cremonesi, L, Forni, GL, Soriani, N, et al. Genetic and clinical heterogeneity of ferroportin disease. Br J Haematol 2005; 131: 6630.CrossRefGoogle ScholarPubMed
Bach, V, Remacha, A, Altes, A, Barcelo, MJ, Molina, MA, Baiget, M. Autosomal dominant hereditary hemochromatosis associated with two novel Ferroportin 1 mutations in Spain. Blood Cells Mol Dis 2006; 36: 41.CrossRefGoogle ScholarPubMed
Wallace, DF, Clark, RM, Harley, HA, Subramaniam, VN. Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis. J Hepatol 2004; 40: 710–13.CrossRefGoogle Scholar
Girelli, D, Domenico, I, Bozzini, C, et al. Clinical, pathological, and molecular correlates in ferroportin disease: a study of two novel mutations. J Hepatol 2008; 49: 6641.CrossRefGoogle ScholarPubMed
Hetet, G, Devaux, I, Soufir, N, Grandchamp, B, Beaumont, C. Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Blood 2003; 102: 1904–10.CrossRefGoogle Scholar
Speletas, M, Kioumi, A, Loules, G, et al. Analysis of SLC40A1 gene at the mRNA level reveals rapidly the causative mutations in patients with hereditary hemochromatosis type IV. Blood Cells Mol Dis 2008; 40: 353–9.CrossRefGoogle ScholarPubMed
Morris, TJ, Litvinova, MM, Ralston, D, Mattman, A, Holmes, D, Lockitch, G. A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis. Blood Cells Mol Dis 2005; 35: 309–14.CrossRefGoogle Scholar
Zaahl, MG, Merryweather-Clarke, AT, Kotze, MJ, , Merwe S, Warnich, L, Robson, KJ. Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload. Hum Genet 2004; 115: 409–17.CrossRefGoogle ScholarPubMed
Robson, KJ, Merryweather-Clarke, AT, Cadet, E, et al. Recent advances in understanding haemochromatosis: a transition state. J Med Genet 2004; 41: 721–30.CrossRefGoogle ScholarPubMed
Lok, CY, Merryweather-Clarke, AT, Viprakasit, V, et al. Iron overload in the Asian community. Blood 2009; 114: 20.CrossRefGoogle ScholarPubMed
Wallace, DF, Dixon, JL, Ramm, GA, Anderson, GJ, Powell, LW, Subramaniam, VN. A novel mutation in ferroportin implicated in iron overload. J Hepatol 2007; 46: 921–6.CrossRefGoogle ScholarPubMed
Lee, PL, Gelbart, T, West, C, Barton, JC.SLC40A1 c.1402G→A results in aberrant splicing, ferroportin truncation after glycine 330, and an autosomal dominant hemochromatosis phenotype. Acta Haematol 2007; 118: 237–41.CrossRefGoogle Scholar
Griffiths, WJ, Mayr, R, McFarlane, I, et al. Clinical presentation and molecular pathophysiology of autosomal dominant hemochromatosis caused by a novel ferroportin mutation. Hepatology 2009, Oct 19. [Epub ahead of print]
Jouanolle, AM, Douabin-Gicquel, V, Halimi, C, et al. Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload. J Hepatol 2003; 39: 286–9.CrossRefGoogle ScholarPubMed
Letocart, E, Gac, G, Majore, S, et al. A novel missense mutation in SLC40A1 results in resistance to hepcidin and confirms the existence of two ferroportin-associated iron overload diseases. Br J Haematol 2009; 147: 379–85.CrossRefGoogle ScholarPubMed
Duca, L, Delbini, P, Nava, I, Vaja, V, Fiorelli, G, Cappellini, MD. Mutation analysis of hepcidin and ferroportin genes in Italian prospective blood donors with iron overload. Am J Hematol 2009; 84: 592–3.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×