Functional and clinical impact of novel Tmprss6 variants in iron-refractory iron-deficiency anemia patients and genotype–phenotype studies
Author
De Falco, Luigia
Silvestri, Laura
Kannengiesser, Caroline
Morán, Erica
Oudin, Claire
Rausa, Marco
Bruno, Mariasole
Aranda, Jessica
Argiles, Bienvenida
Yenicesu, Idil
Falcon-Rodriguez, Maria
Yilmaz-Keskin, Ebru
Kocak, Ulker
Beaumont, Carole
Camaschella, Clara
Iolascon, Achille
Grandchamp, Bernard
Sanchez, Mayka
Publication date
2014ISSN
1059-7794
Abstract
Iron-refractory iron-deficiency anemia (IRIDA) is a rare autosomal-recessive disorder characterized by hypochromic microcytic anemia, low transferrin saturation, and inappropriate high levels of the iron hormone hepcidin. The disease is caused by variants in the transmembrane protease serine 6 (TMPRSS6) gene that encodes the type II serine protease matriptase-2, a negative regulator of hepcidin transcription. Sequencing analysis of the TMPRSS6 gene in 21 new IRIDA patients from 16 families with different ethnic origin reveal 17 novel mutations, including the most frequent mutation in Southern Italy (p.W590R). Eight missense mutations were analyzed in vitro. All but the p.T287N variant impair matriptase-2 autoproteotylic activation, decrease the ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation. Genotype–phenotype studies in IRIDA patients have been so far limited due to the relatively low number of described patients. Our genotype–phenotype correlation analysis demonstrates that patients carrying two nonsense mutations present a more severe anemia and microcytosis and higher hepcidin levels than the other patients. We confirm that TMPRSS6 mutations are spread along the gene and that mechanistically they fully or partially abrogate hepcidin inhibition. Genotyping IRIDA patients help in predicting IRIDA severity and may be useful for predicting response to iron treatment.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
61 - Medical sciences
Keywords
Medicina
Medicina
Medicine
Pages
8
Publisher
Wiley
Collection
35;11
Is part of
Human Mutation
Citation
De Falco, Luigia; Silvestri, Laura; Kannengiesser, Caroline [et al.]. Functional and Clinical Impact of Novel Tmprss6 Variants in Iron-Refractory Iron-Deficiency Anemia Patients and Genotype–Phenotype Studies. Human Mutation, 2014, 35(11), p. 1321-1329. Disponible en: <https://onlinelibrary.wiley.com/doi/10.1002/humu.22632>. Fecha de acceso: 22 ene. 2024. DOI: 10.1002/humu.22632
This item appears in the following Collection(s)
- Ciències de la Salut [725]
Rights
© 2014 WILEY PERIODICALS, INC.