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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Novel TMPRSS6 mutations associated with Iron-refractory Iron Deficiency Anemia (IRIDA)
Human Mutation, Volume 31, No. 5, Year 2010
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Description
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.
Authors & Co-Authors
De Falco, Luigia
Italy, Naples
Ceinge-biotecnologie Avanzate S.c.a R.l.
Totaro, Francesca
Italy, Naples
Ceinge-biotecnologie Avanzate S.c.a R.l.
Nai, Antonella
Italy, Milan
Università Vita-salute San Raffaele
Pagani, Alessia
Italy, Milan
Università Vita-salute San Raffaele
Girelli, Domenico
Italy, Verona
Università Degli Studi Di Verona
Silvestri, Laura
Italy, Milan
Università Vita-salute San Raffaele
Piscopo, Carmelo
Italy, Naples
Ceinge-biotecnologie Avanzate S.c.a R.l.
Campostrini, Natascia
Italy, Verona
Università Degli Studi Di Verona
Dufour, Carlo
Italy, Genoa
Istituto Giannina Gaslini
Al-Manjomi, Fahad M.
Saudi Arabia, Riyadh
King Fahad Medical City
Minkov, Milen
Austria, Vienna
Sant'anna Children's Hospital
Van Vuurden, Dennis G.
Netherlands, Amsterdam
Amsterdam Umc - Vrije Universiteit Amsterdam
Feliu, Aurora
Argentina, Buenos Aires
Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan
Kattamis, Antonis C.
Greece, Athens
School of Medicine
Camaschella, Clara
Italy, Milan
Università Vita-salute San Raffaele
Iolascon, Achille
Italy, Naples
Ceinge-biotecnologie Avanzate S.c.a R.l.
Italy, Naples
Università Degli Studi Di Napoli Federico Ii
Statistics
Citations: 62
Authors: 16
Affiliations: 10
Identifiers
Doi:
10.1002/humu.21243
ISSN:
10597794
e-ISSN:
10981004
Research Areas
Cancer
Genetics And Genomics