A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA.

Sandro Altamura , Flavia d'Alessio , Barbara Selle , Martina Muckenthaler (1)

1 Head of Molecular Medicine

IRIDA (Iron-Refractory Iron Deficiency Anemia) is a rare, autosomal recessive disorder hallmarked by hypochromic, microcytic anemia, low transferrin saturation and high levels of the iron-regulated hormone hepcidin. The disease is caused by mutations in the transmembrane serine-protease TMPRSS6 that prevent inactivation of Hemojuvelin (HJV), an activator of hepcidin transcription. Here we report a patient with IRIDA that carries a novel mutation (Y141C) in the SEA domain of the TMPRSS6 gene. Functional characterization of the TMPRSS6(Y141C) mutant protein in cultured cells shows that it localizes to similar subcellular compartments like wild-type TMPRSS6, binds HJV and but fails to auto-catalytically activate itself. As a consequence, hepcidin mRNA expression is increased causing the clinical symptoms observed in this IRIDA patient. This study yields important mechanistic insight into how TMPRSS6 is activated.

Mots clés: Life Sciences

Sandro Altamura, Flavia d'Alessio, Barbara Selle, Martina Muckenthaler. A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA.. Biochemical Journal, 2010, 431 (3), pp.363-371. ⟨10.1042/BJ20100668⟩. ⟨hal-00525044⟩