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

• A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis [6].
• Missense mutations in ferroportin1 (fpn1), an intestinal and macrophage iron exporter, have been identified between transmembrane helices 3 and 4 in the zebrafish anemia mutant weissherbst (weh(Tp85c-/-)) and in patients with type 4 hemochromatosis [7].
• To explore the effects of fpn1 mutation on blood development and iron homeostasis in the adult zebrafish, weh(Tp85c-/-) zebrafish were rescued by injection with iron dextran and studied in comparison with injected and uninjected WT zebrafish and heterozygotes [7].
• The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores [8].
• Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload [9].

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

• RECENT FINDINGS: Hepcidin antimicrobial peptide likely modulates iron transport from macrophages and enterocytes to red blood cell precursors as a consequence of its interaction with SLC40A1/ferroportin, the only known transporter that facilitates iron egress [13].
• Whether ferroportin functions in this process at other sites in the enterocyte is unknown [14].
• Ferroportin expression was determined by western blot analysis of duodenal mucosa enriched microvillus membranes, Caco-2 cells, IEC-6 cells, and freshly isolated enterocytes [14].
• Ferroportin protein was enriched in microvillus membrane preparations [14].
• Ferroportin was seen in the basal cytoplasm and along the basolateral membranes [14].

Associations of SLC40A1 with chemical compounds

• It was located in the noncoding region of the ferroportin 1; nucleotide 117 adenine was changed to guanine, 7 nucleotides downstream the iron responsive element (IRE) region [15].
• Exposure of the cells to iron (200 micromol/L ferric nitrilotriacetic acid for 72 h) significantly decreased transferrin receptor mRNA (80%), DMT1 mRNA (57%) and IREG1 mRNA (52%) [16].
• RESULTS: Iron increased and desferrioxamine decreased luciferase activity in all the cell types using both the full-length construct and the promoter deletion constructs, in the absence of changes in SLC40A1 or luciferase mRNA levels [12].
• Tumor necrosis factor-alpha significantly increased mRNA levels of TfR2 and decreased those of DMT1 and IREG1 [17].
• Our data further indicates upregulation of DMT-1 and IREG-1 mRNA and protein in response to high levels of glucose [18].

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

• BACKGROUND & AIMS: An increased duodenal expression of the iron transporters, divalent-metal-transporter-1, and ferroportin is observed in patients with iron deficiency or hereditary hemochromatosis [22].
• In Africans with iron overload not related to the HFE gene, the possible involvement of the SLC40A1 and CYBRD1 genes was demonstrated for the first time [1].
• RESULTS:: Physiological iron overload led to significantly upregulated hepcidin, HJV and ferroportin mRNA expression while TfR2 expression was not significantly different to controls [23].
• A Japanese family with ferroportin disease caused by a novel mutation of SLC40A1 gene: hyperferritinemia associated with a relatively low transferrin saturation of iron [24].
• METHODS: DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of TaqMan real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry [9].

Analytical, diagnostic and therapeutic context of SLC40A1

• However, phlebotomy may not be well tolerated in certain forms of non-HFE hemochromatosis such as "ferroportin disease."[25]
• Denaturing high-performance liquid chromatography was employed to scan for the SLC40A1 gene [26].
• Confocal microscopy showed DMT1 and IREG1 on the cell membrane of IEC-6 cells at 4 degrees C but at intracellular locations at 37 degrees C, indicating that these proteins can function at the cell membrane and intracellularly [27].
• Using quantitative PCR, we measured mRNA expression of divalent cation transporter 1 (DCT1), iron-regulated gene 1 (IREG1), and hephaestin in duodenal biopsy samples of individuals with normal iron levels, iron-deficiency anemia, or iron overload [28].
• Heterozygosity for the ferroportin Val 162 deletion represents the prototype of selective reticuloendothelial iron overload, and should be taken into account in the differential diagnosis of hereditary or congenital hyperferritinaemias [29].

References