Disease relevance of Heph

• We compared iron levels and expression of genes involved in iron uptake and storage in sla mice and C57BL/6J mice fed iron-deficient, iron-overload, or control diets [1].
• The anaemia in newborn sla mice is attributable to iron deficiency, since their total body iron is lower than in normal newborn mice, while their birth weights are almost identical [2].
• Using the Jackson Laboratory BSS panel, we have localized Praja1 on chromosome X at 36 cM, which may be a candidate gene for mouse sla (sex linked sideroblastic anemia), near the X inactivation center gene, Xist [3].
• The duodenal mucosa of genotypically normal iron replete and iron deficient mice and mice with sex-linked (sla) and microcytic anemias (mk) was examined for the presence of iron-binding proteins [4].
• We have identified an animal model, the 'sex-linked anemic' (gene symbol, sla) mouse, characterized by iron deficiency anemia, to study the relationship between anemia and cholesterol metabolism [5].

High impact information on Heph

• We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine [6].
• CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium [7].
• We suggest that hephaestin, by way of its ferroxidase activity, facilitates iron export from intestinal enterocytes, most likely in cooperation with the basolateral iron transporter, Ireg1 [8].
• Here, we demonstrate that Hp has both amine oxidase and ferroxidase activity in cultured cells and primary intestinal enterocytes with the use of both gel and solution assays [8].
• Molecular modeling of the truncated hephaestin suggests retention of a minimum catalytic core required for enzymatic activity [8].

Biological context of Heph

• The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals [9].
• We have precisely mapped the sla locus within the central region of the X chromosome in relation to a panel of microsatellite markers [10].
• Haemoglobin levels at birth in normal, anaemic and carrier mice are also influenced by the mother's genotype and phenotype, and the haemoglobin value was progressively lower according to the sla gene dose of the mother [2].
• Iron accumulation in mice deficient in ceruloplasmin and hephaestin was associated with upregulation of ferritin and ferroportin [11].
• Expression of full-length hephaestin could complement the low-iron growth phenotype of a Delta fet3 strain [12].

Anatomical context of Heph

• Unlike iron-deficient mice, sla mouse enterocytes accumulated nonheme iron and ferritin [1].
• CONCLUSION: We suggest that mislocalisation of hephaestin likely contributes to the functional defect in sla intestinal epithelium [13].
• We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity [9].
• The sla gene is already known to have a major effect in reducing iron transport in the small intestine [2].
• Analysis of the sla mouse has supported our model for the regulation of intestinal iron absorption whereby changes in systemic iron requirements alter the levels of basolateral transport components with subsequent regulation of brush border transport [14].

Associations of Heph with chemical compounds

• For example, copper-containing proteins like ceruloplasmin and hephaestin oxidize Fe(2+) during cellular export processes for transport in the circulation bound to transferrin [15].
• Parenteral iron administration produced an increase in the duodenal, liver, and splenic ferritin concentration in both sla/Y and +/Y animals that was most striking in the case of the liver [16].
• Relationship between anemia and cholesterol metabolism in 'sex-linked anemic' (gene symbol, sla) mouse [5].

Physical interactions of Heph

• Hephaestin is a membrane-bound multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation [1].

Regulatory relationships of Heph

• In contrast, the iron permease Ireg1 localised to the basolateral membrane in both control and sla mice [13].

Other interactions of Heph

• Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency [1].
• In the HT versus H comparison, only a few genes were found that had increased expression in the HT line compared with expression in the H line, including GSH-S-transferase alpha 3 and hephaestin [17].

Analytical, diagnostic and therapeutic context of Heph

• In sla mice, in spite of tissue iron deficiency, the amount of iron deposited was similar to that of normal mice and markedly increased after treatment of the anemia [18].
• Using electron microscopy radioautography, the deposition of intravenously administered iron in the duodenal epithelium was studied in normal mice, iron-overloaded and iron-deficient mice, and in mice with X-linked anemia (gene symbol sla) 4 and 24 hours after injection of 59Fe [18].

References