@article{3089459,
    title = "Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA)",
    author = "De Falco, L. and Totaro, F. and Nai, A. and Pagani, A. and Girelli, D. and Silvestri, L. and Piscopo, C. and Campostrini, N. and Dufour, C. and Al Manjomi, F. and Minkov, M. and Van Vuurden, D.G. and Feliu, A. and Kattamis, A. and Camaschella, C. and Iolascon, A.",
    journal = "Human Mutation",
    year = "2010",
    volume = "31",
    number = "5",
    pages = "E1390-E1405",
    issn = "1059-7794, 1098-1004",
    doi = "10.1002/humu.21243",
    keywords = "ferrous gluconate;  hepcidin;  iron;  matriptase;  matriptase 2;  messenger RNA;  unclassified drug, article;  child;  clinical article;  computer model;  controlled study;  disease severity;  female;  frameshift mutation;  gene activation;  gene expression;  gene mutation;  genetic conservation;  genotype phenotype correlation;  human;  iron deficiency anemia;  iron refractory iron deficiency anemia;  male;  missense mutation;  nonsense mutation;  nucleotide sequence;  preschool child;  priority journal;  promoter region;  protein degradation;  protein domain;  school child;  silent mutation, Anemia, Iron-Deficiency;  Antimicrobial Cationic Peptides;  Child;  Child, Preschool;  DNA Mutational Analysis;  Enzyme Activation;  Female;  Frameshift Mutation;  Humans;  Male;  Membrane Proteins;  Mutation, Missense;  Pedigree;  Serine Endopeptidases",
    abstract = "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."
}