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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5605-5608. Prepublished online as a Blood First Edition Paper on April 8, 2009; DOI 10.1182/blood-2008-12-195594. This Article Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-12-195594v1 113/22/5605    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Silvestri, L. Articles by Grandchamp, B. Search for Related Content PubMed PubMed Citation Articles by Silvestri, L. Articles by Grandchamp, B. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 22, 2008 Accepted March 27, 2009 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, and Bernard Grandchamp* Vita-Salute University - San Raffaele Scientific Institute, Milan, Italy INSERM UMR773, University Paris Diderot, Paris, France APHP, Hopital Xavier Bichat, Service de Biochimie Hormonale et Genetique, Paris, France Groupe Hospitalier du Havre, Service d'Hematologie Biologique, Le Havre, France Groupe Hospitalier du Havre, Departement de Pediatrie, Le Havre, France * Corresponding author; email: bernard.grandchamp{at}inserm.fr. 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 two missense mutations in the second LDLRA domain. Functional studies of these two mutations and of a previously reported mutation in the second CUB domain were performed. Transfection of mutant cDNAs showed that membrane-targeting of the two LDLRA mutants was impaired, with Golgi retention of the variants. The activating cleavage was absent for the LDLRA mutants, and reduced for the CUB mutant. All three mutated proteins were still able to physically interact with hemojuvelin but only partially repressed hepcidin expression as compared to wild type matriptase-2. Our results underline the importance of LDLRA and CUB domains of matriptase-2. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. J. Ramsay, V. Quesada, M. Sanchez, C. Garabaya, M. P. Sarda, M. Baiget, A. Remacha, G. Velasco, and C. Lopez-Otin Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms Hum. Mol. Genet., October 1, 2009; 18(19): 3673 - 3683. [Abstract] [Full Text] [PDF]

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