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Gene Review

SLC40A1  -  solute carrier family 40 (iron-regulated...

Homo sapiens

Synonyms: FPN1, Ferroportin-1, HFE4, IREG1, Iron-regulated transporter 1, ...
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Disease relevance of SLC40A1

  • We identified a novel D270V mutation in the SLC40A1 gene in a Black South African female with iron overload [1].
  • Expression of DMT1 and Ireg1 was increased 1.5 to 3-fold in subjects with cirrhosis compared with iron-replete control subjects [2].
  • In cirrhosis, the expression of DMT1 and Ireg1 was not related to the severity of liver disease or cirrhosis type [2].
  • There was no correlation between the duodenal expression of DMT1 and Ireg1 and the degree of hepatic siderosis [2].
  • No rare variants at 15 more loci at HFE, TFR2, and FPN1 were observed in breast cancer patients [3].
  • The S338R mutation results in a mutated ferroportin associated with iron overload and is predicted insensitive to regulation by the iron regulatory hormone hepcidin [4].
  • Non-classical ferroportin disease is associated with a higher risk of fibrosis and a more severe overload of hepatic iron [5].

High impact information on SLC40A1


Biological context of SLC40A1

  • CONCLUSIONS: DMT1 and FP1 are centrally involved in iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload [9].
  • BACKGROUND AND AIMS: While upregulation of divalent metal transporter 1 (DMT1) and iron regulated gene 1 (IREG1) within duodenal enterocytes is reported in patients with hereditary haemochromatosis (HH), these findings are controversial [10].
  • CONCLUSIONS: These findings demonstrate that untreated HH patients do not have increased duodenal DMT1 and IREG mRNA, but rather phlebotomy increases expression of these molecules, reflecting the effect of phlebotomy induced erythropoiesis [10].
  • Ferroportin protein expression was increased in C282Y homozygotes (n = 23) compared to wild-type patients (n = 37) (P < 0.003) [11].
  • CONCLUSIONS: We demonstrate that the iron responsive element in the SLC40A1 gene is functional and that it controls gene expression through the cytoplasmic iron regulatory protein system [12].

Anatomical context of SLC40A1


Associations of SLC40A1 with chemical compounds


Physical interactions of SLC40A1

  • The basolateral transfer of iron requires two components: a copper-containing iron oxidase known as hephaestin and a membrane transport protein IREG1 [19].

Regulatory relationships of SLC40A1

  • At the same time, IFN-gamma and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes [20].
  • The mRNAs for TfR-1 and, potentially, FPN-1 are posttranscriptionally regulated by iron regulatory protein (IRP)-1 and IRP-2 [21].

Other interactions of SLC40A1


Analytical, diagnostic and therapeutic context of SLC40A1


  1. Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload. Zaahl, M.G., Merryweather-Clarke, A.T., Kotze, M.J., van der Merwe, S., Warnich, L., Robson, K.J. Hum. Genet. (2004) [Pubmed]
  2. Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis. Stuart, K.A., Anderson, G.J., Frazer, D.M., Murphy, T.L., Powell, L.W., Fletcher, L.M., Crawford, D.H. Hepatology (2004) [Pubmed]
  3. Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer. Abraham, B.K., Justenhoven, C., Pesch, B., Harth, V., Weirich, G., Baisch, C., Rabstein, S., Ko, Y.D., Brüning, T., Fischer, H.P., Haas, S., Brod, S., Oberkanins, C., Hamann, U., Brauch, H. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  4. A novel mutation in ferroportin implicated in iron overload. Wallace, D.F., Dixon, J.L., Ramm, G.A., Anderson, G.J., Powell, L.W., Subramaniam, V.N. J. Hepatol. (2007) [Pubmed]
  5. Ferroportin disease: a systematic meta-analysis of clinical and molecular findings. Mayr, R., Janecke, A.R., Schranz, M., Griffiths, W.J., Vogel, W., Pietrangelo, A., Zoller, H. J. Hepatol. (2010) [Pubmed]
  6. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Njajou, O.T., Vaessen, N., Joosse, M., Berghuis, B., van Dongen, J.W., Breuning, M.H., Snijders, P.J., Rutten, W.P., Sandkuijl, L.A., Oostra, B.A., van Duijn, C.M., Heutink, P. Nat. Genet. (2001) [Pubmed]
  7. Ferroportin1 is required for normal iron cycling in zebrafish. Fraenkel, P.G., Traver, D., Donovan, A., Zahrieh, D., Zon, L.I. J. Clin. Invest. (2005) [Pubmed]
  8. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. Montosi, G., Donovan, A., Totaro, A., Garuti, C., Pignatti, E., Cassanelli, S., Trenor, C.C., Gasparini, P., Andrews, N.C., Pietrangelo, A. J. Clin. Invest. (2001) [Pubmed]
  9. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Zoller, H., Koch, R.O., Theurl, I., Obrist, P., Pietrangelo, A., Montosi, G., Haile, D.J., Vogel, W., Weiss, G. Gastroenterology (2001) [Pubmed]
  10. Increased DMT1 but not IREG1 or HFE mRNA following iron depletion therapy in hereditary haemochromatosis. Kelleher, T., Ryan, E., Barrett, S., Sweeney, M., Byrnes, V., O'Keane, C., Crowe, J. Gut (2004) [Pubmed]
  11. Expression of ferroportin in hemochromatosis liver. Adams, P.C., Barbin, Y.P., Khan, Z.A., Chakrabarti, S. Blood Cells Mol. Dis. (2003) [Pubmed]
  12. The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. Lymboussaki, A., Pignatti, E., Montosi, G., Garuti, C., Haile, D.J., Pietrangelo, A. J. Hepatol. (2003) [Pubmed]
  13. Anemia of inflammation: the hepcidin link. Roy, C.N., Andrews, N.C. Curr. Opin. Hematol. (2005) [Pubmed]
  14. Ferroportin/IREG-1/MTP-1/SLC40A1 modulates the uptake of iron at the apical membrane of enterocytes. Thomas, C., Oates, P.S. Gut (2004) [Pubmed]
  15. Hemochromatosis with mutation of the ferroportin 1 (IREG1) gene. Liu, W., Shimomura, S., Imanishi, H., Iwamoto, Y., Ikeda, N., Saito, M., Ohno, M., Hara, N., Yamamoto, T., Nakamura, H., Hada, T. Intern. Med. (2005) [Pubmed]
  16. Iron treatment downregulates DMT1 and IREG1 mRNA expression in Caco-2 cells. Martini, L.A., Tchack, L., Wood, R.J. J. Nutr. (2002) [Pubmed]
  17. Regulatory effects of tumor necrosis factor-alpha and interleukin-6 on HAMP expression in iron loaded rat hepatocytes. Dzikaite, V., Holmström, P., Stål, P., Eckes, K., Hagen, K., Eggertsen, G., Gåfvels, M., Melefors, O., Hultcrantz, R. J. Hepatol. (2006) [Pubmed]
  18. Glucose-induced regulation of novel iron transporters in vascular endothelial cell dysfunction. Khan, Z.A., Farhangkhoee, H., Barbin, Y.P., Adams, P.C., Chakrabarti, S. Free Radic. Res. (2005) [Pubmed]
  19. The expression and regulation of the iron transport molecules hephaestin and IREG1: implications for the control of iron export from the small intestine. Anderson, G.J., Frazer, D.M., McKie, A.T., Wilkins, S.J., Vulpe, C.D. Cell Biochem. Biophys. (2002) [Pubmed]
  20. Cytokine-mediated regulation of iron transport in human monocytic cells. Ludwiczek, S., Aigner, E., Theurl, I., Weiss, G. Blood (2003) [Pubmed]
  21. Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta. Bradley, J., Leibold, E.A., Harris, Z.L., Wobken, J.D., Clarke, S., Zumbrennen, K.B., Eisenstein, R.S., Georgieff, M.K. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  22. Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Zoller, H., Theurl, I., Koch, R.O., McKie, A.T., Vogel, W., Weiss, G. Gastroenterology (2003) [Pubmed]
  23. Hepatic iron metabolism gene expression profiles in HFE associated Hereditary Hemochromatosis. Gleeson, F., Ryan, E., Barrett, S., Russell, J., Crowe, J. Blood Cells Mol. Dis. (2007) [Pubmed]
  24. A Japanese family with ferroportin disease caused by a novel mutation of SLC40A1 gene: hyperferritinemia associated with a relatively low transferrin saturation of iron. Koyama, C., Wakusawa, S., Hayashi, H., Ueno, T., Suzuki, R., Yano, M., Saito, H., Okazaki, T. Intern. Med. (2005) [Pubmed]
  25. Iron Overload (with Attention to Genetic Testing and Diagnosis/Management of HFE Wild Type Patients). Siddaiah, N., Kowdley, K.V. Current treatment options in gastroenterology (2006) [Pubmed]
  26. Genetic and clinical heterogeneity of ferroportin disease. Cremonesi, L., Cemonesi, L., Forni, G.L., Soriani, N., Lamagna, M., Fermo, I., Daraio, F., Galli, A., Pietra, D., Malcovati, L., Ferrari, M., Camaschella, C., Cazzola, M. Br. J. Haematol. (2005) [Pubmed]
  27. IEC-6 cells are an appropriate model of intestinal iron absorption in rats. Thomas, C., Oates, P.S. J. Nutr. (2002) [Pubmed]
  28. Intestinal expression of genes involved in iron absorption in humans. Rolfs, A., Bonkovsky, H.L., Kohlroser, J.G., McNeal, K., Sharma, A., Berger, U.V., Hediger, M.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  29. Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3). Cazzola, M., Cremonesi, L., Papaioannou, M., Soriani, N., Kioumi, A., Charalambidou, A., Paroni, R., Romtsou, K., Levi, S., Ferrari, M., Arosio, P., Christakis, J. Br. J. Haematol. (2002) [Pubmed]
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