Defective SLC40A1 does not transport Fe3+ from extracellular region to cytosol

Stable Identifier
Reaction [transition]
Homo sapiens
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The primary site for absorption of dietary iron is the duodenum. Ferrous iron (Fe2+) is taken up from the gut lumen across the apical membranes of enterocytes and released into the portal vein circulation across basolateral membranes. The human gene SLC40A1 encodes the metal transporter protein MTP1 (aka ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein. SLC40A1 colocalises with hephaestin (HEPH) which stablises it and is necessary for the efflux reaction to occur.
Defects in SLC40A1 can cause hemochromatosis 4 (HFE4; MIM:606069), a disorder of iron metabolism characterised by iron overload. Excess iron is deposited in a variety of organs leading to their failure, resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis and hypogonadotropic hypogonadism. Severe effects of the disease don't usually appear until after decades of progressive iron overloading. Mutations causing HFE4 include N144H, A77D, V162del, G80V, D181V and D157G (Njajou et al. 2001, Agarwal et al. 2006, Wallace et al. 2002, Cremonesi et al. 2005, Hetet et al. 2003).

Literature References
PubMed ID Title Journal Year
12091366 Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis

Stephenson, P, Subramaniam, VN, Dixon, JL, Pedersen, P, Wallace, DF, Searle, JW, Powell, LW

Blood 2002
16351644 Genetic and clinical heterogeneity of ferroportin disease

Cemonesi, L, Cremonesi, L, Ferrari, M, Galli, A, Lamagna, M, Fermo, I, Pietra, D, Soriani, N, Forni, GL, Daraio, F, Cazzola, M, Camaschella, C, Malcovati, L

Br. J. Haematol. 2005
16813613 Ferroportin (SLC40A1) gene in thalassemic patients of Indian descent

Pradhan, M, Tewari, D, Sankar, VH, Agarwal, S

Clin. Genet. 2006
12730114 Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations

Beaumont, C, Hetet, G, Devaux, I, Soufir, N, Grandchamp, B

Blood 2003
11431687 A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis

Oostra, BA, Rutten, WP, Snijders, PJ, Vaessen, N, Breuning, MH, Joosse, M, Berghuis, B, Heutink, P, van Duijn, CM, Njajou, OT, Sandkuijl, LA, van Dongen, JW

Nat. Genet. 2001
Catalyst Activity

ferrous iron transmembrane transporter activity of HEPH:6xCu2+:SLC40A1 mutants [plasma membrane]

Normal reaction
Functional status

Loss of function of HEPH:6xCu2+:SLC40A1 mutants [plasma membrane]

Name Identifier Synonyms
hemochromatosis DOID:2352 iron storage disorder, Hemochromatosis (disorder), diabetes bronze, Bronze diabetes (disorder), HEMOCHROMATOSIS, Hemochromatosis (disorder), Bronzed diabetes, Haemochromatosis, Haemochromatosis
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