Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia

Laura Silvestri, Flavia Guillem, Alessia Pagani, Antonella Nai, Claire Oudin, Muriel Silva, Fabienne Toutain, Caroline Kannengiesser, Carole Beaumont, Clara Camaschella, Bernard Grandchamp

Research output: Contribution to journalArticle

Abstract

Matriptase-2 is a transmembrane serine protease that negatively regulates hepcidin expression by cleaving membrane-bound hemojuvelin. Matriptase-2 has a complex ectodomain, including a C-terminal serine protease domain and its activation requires an autocatalytic cleavage. Matriptase-2 mutations have been reported in several patients with iron-refractory iron deficiency anemia. Here we describe a patient with 2 missense mutations in the second classA low-density lipoprotein receptor (LDLRA) domain. Functional studies of these 2 mutations and of a previously reported mutation in the second C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1 (CUB) domain were performed. Transfection of mutant cDNAs showed that membrane targeting of the 2 LDLRAmutants was impaired, with Golgi retention of the variants. The activating cleavage was absent for the LDLRA mutants and reduced for the CUB mutant. All 3 mutated proteins were still able to physically interact with hemojuvelin but only partially repressed hepcidin expression compared with wild-type matriptase-2. Our results underline the importance of LDLRA and CUB domains of matriptase-2.

Original languageEnglish
Pages (from-to)5605-5608
Number of pages4
JournalBlood
Volume113
Issue number22
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Silvestri, L., Guillem, F., Pagani, A., Nai, A., Oudin, C., Silva, M., Toutain, F., Kannengiesser, C., Beaumont, C., Camaschella, C., & Grandchamp, B. (2009). Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood, 113(22), 5605-5608. https://doi.org/10.1182/blood-2008-12-195594