NOVEL TMPRSS6 MUTATIONS ASSOCIATED WITH IRON-REFRACTORY IRON DEFICIENCY ANEMIA (IRIDA)

Luigia de Falco (1) , Francesca Totaro (1) , Antonella Nai (2) , Alessia Pagani (2) , Domenico Girelli (3) , Laura Silvestri (2) , Carmelo Piscopo (1) , Natascia Campostrini (3) , Carlo Dufour (4) , Fahd Al Manjomi (5) , Milen Minkov (6) , Dennis G. van Vuurden (7) , Aurora Feliu (8) , Antonis Kattamis (9) , Clara Camaschella (2) , Achille Iolascon (1, 10)

1 Ceinge, centro di Ingegneria Genetica e Biotecnologie Avanzate
2 San Raffaele Scientific Institute
3 Department of Clinical and Experimental Medicine
4 Dipartimento di Ematologia e Oncologia Pediatrica
5 Head of Pediatric Hematology/Oncology Department
6 Sant'Anna Children's Hospital
7 Department of Pediatrics
8 Hospital de Pediatria Combate de los Pozos
9 First department of Pediatrics
10 Dipartimento di Biochimica e Biotecnologie Mediche

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 demonstrating a reduced inhibitory effect for the former mutation, but surprisingly a normal function for R271Q which appears silent 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 mutations.

Mots clés: Life Sciences

Luigia de Falco, Francesca Totaro, Antonella Nai, Alessia Pagani, Domenico Girelli, et al.. NOVEL TMPRSS6 MUTATIONS ASSOCIATED WITH IRON-REFRACTORY IRON DEFICIENCY ANEMIA (IRIDA). Human Mutation, 2010, 31 (5), ⟨10.1002/humu.21243⟩. ⟨hal-00552375⟩