The iron hormone hepcidin is inhibited by matriptase-2, a liver serine-protease encoded by TMPRSS6 gene. Cleaving the BMP-coreceptor hemojuvelin, matriptase-2 impairs the BMP/SMAD signaling pathway, downregulates hepcidin and facilitates iron absorption. TMPRSS6 inactivation causes iron-deficiency-anemia refractory to iron administration both in humans and mice. Genome wide association studies have shown that the SNP rs855791, which causes the matriptase-2 V736A amino acid substitution, is associated with variations of serum iron, transferrin saturation, hemoglobin and erythrocyte traits. Here we show that in vitro matriptase-2 736A inhibits hepcidin more efficiently than 736V . Moreover, in a genotyped population, after exclusion of samples with iron deficiency and inflammation, hepcidin, hepcidin/transferrin saturation and hepcidin/ferritin ratios were significantly lower and iron parameters were consistently higher in homozygotes 736A than in 736V. Our results indicate that rs855791 is a TMPRSS6 functional variant and strengthen that even a partial inability to modulate hepcidin influences iron parameters and indirectly erythropoiesis.

TMPRSS6 rs855791 modulates hepcidin transcription in vitro and levels of serum hepcidin according to iron status in normal individuals

TRAGLIA, MICHELA;
2011-01-01

Abstract

The iron hormone hepcidin is inhibited by matriptase-2, a liver serine-protease encoded by TMPRSS6 gene. Cleaving the BMP-coreceptor hemojuvelin, matriptase-2 impairs the BMP/SMAD signaling pathway, downregulates hepcidin and facilitates iron absorption. TMPRSS6 inactivation causes iron-deficiency-anemia refractory to iron administration both in humans and mice. Genome wide association studies have shown that the SNP rs855791, which causes the matriptase-2 V736A amino acid substitution, is associated with variations of serum iron, transferrin saturation, hemoglobin and erythrocyte traits. Here we show that in vitro matriptase-2 736A inhibits hepcidin more efficiently than 736V . Moreover, in a genotyped population, after exclusion of samples with iron deficiency and inflammation, hepcidin, hepcidin/transferrin saturation and hepcidin/ferritin ratios were significantly lower and iron parameters were consistently higher in homozygotes 736A than in 736V. Our results indicate that rs855791 is a TMPRSS6 functional variant and strengthen that even a partial inability to modulate hepcidin influences iron parameters and indirectly erythropoiesis.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2710498
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