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Novel TMPRSS6 mutations associated with iron‐refractory iron deficiency anemia (IRIDA)
Author(s) -
De Falco Luigia,
Totaro Francesca,
Nai Antonella,
Pagani Alessia,
Girelli Domenico,
Silvestri Laura,
Piscopo Carmelo,
Campostrini Natascia,
Dufour Carlo,
Manjomi Fahd AL,
Minkov Milen,
Van Vuurden Dennis G.,
Feliu Aurora,
Kattamis Antonis,
Camaschella Clara,
Iolascon Achille
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21243
Subject(s) - frameshift mutation , missense mutation , biology , genetics , mutation , tmprss6 , in silico , hepcidin , gene , biochemistry , immunology , serine protease , protease , inflammation , enzyme
Mutations leading to abrogation of matriptase‐2 proteolytic activity in humans are associated with an iron‐refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. In this paper we describe 12 IRIDA patients belonging to 7 unrelated families and identify 10 (9 novel) TMPRSS6 mutations spread along the gene sequence: 5 missense, 1 non sense and 4 frameshift. The frameshift and non sense mutations are predict to result in truncated protein lacking the catalytic domain. The causal role of missense mutations (Y141C, I212T, R271Q, S304L and C510S) is demonstrated by in silico analysis, their absence in 100 control chromosomes and the high conservation of the involved residues. The C510S mutation in the LDLRA domain in silico model causes an intra‐molecular structural imbalance that impairs matriptase‐2 activation. We also assessed the in vitro effect on hepcidin promoter and the proteolytic activity of I212T and R271Q variants demonstrating a reduced inhibitory effect for the former mutation, but surprisingly a normal function for R271Q which appears a silent mutation in vitro. Based on mRNA expression studies I212T could also decrease the total amount of protein produced, likely interfering with mRNA stability. Collectively, our results extend the pattern of TMPRSS6 mutations associated with IRIDA and propose a model of causality for some of the novel missense mutation. © 2010 Wiley‐Liss, Inc.