SEARCH:   Advanced

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 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 Citation Map 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 Google Scholar Articles by Silvestri, L. Articles by Grandchamp, B. PubMed PubMed Citation Articles by Silvestri, L. Articles by Grandchamp, B. Related Collections Red Cells, Iron, and Erythropoiesis Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS Brief report Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia Laura Silvestri1, Flavia Guillem2, Alessia Pagani1, Antonella Nai1, Claire Oudin3, Muriel Silva4, Fabienne Toutain5, Caroline Kannengiesser2,3, Carole Beaumont2, Clara Camaschella1, and Bernard Grandchamp2,3 1 Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy; 2 Inserm UMR773, University Paris Diderot, site Bichat, Paris, France; 3 Assistance Publique-Hopitaux de Paris, Hôpital Xavier Bichat, Service de Biochimie Hormonale et Génétique, Paris, France; and 4 Service d'Hématologie Biologique and 5 Département de Pédiatrie, Groupe Hospitalier du Havre, Le Havre, France 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 class A 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 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 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. 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]

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020