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Blood. 2009 May 28;113(22):5605-8. doi: 10.1182/blood-2008-12-195594. Epub 2009 Apr 8.

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

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Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy.


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.

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