Functional and clinical impact of novel Tmprss6 variants in iron-refractory iron-deficiency Anemia patients and genotype-phenotype studies

Luigia de Falco, Laura Silvestri, Caroline Kannengiesser, Erica Morán, Claire Oudin, Marco Rausa, Mariasole Bruno, Jessica Aranda, Bienvenida Argiles, Idil Yenicesu, Maria Falcon-Rodriguez, Ebru Yilmaz-Keskin, Ulker Kocak, Carole Beaumont, Clara Camaschella, Achille Iolascon, Bernard Grandchamp, Mayka Sanchez

Research output: Contribution to journalArticle

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. Iron-refractory iron-deficiency anemia (IRIDA) is a rare autosomal-recessive disorder caused by TMPRSS6 mutations and characterized by hypochromic microcytic anemia, low transferrin saturation, and inappropriate high levels of the iron hormone hepcidin. We report 17 novel mutations in 21 new IRIDA patients. Functional studies indicate that TMPRSS6 mutations fully or partially abrogate hepcidin inhibition. Genotyping IRIDA patients help in predicting IRIDA severity and may be useful for predicting response to iron treatment.

Original languageEnglish
Pages (from-to)1321-1329
Number of pages9
JournalHuman Mutation
Volume35
Issue number11
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • Functional studies
  • Genotype-phenotype
  • IRIDA
  • Iron-refractory anemia
  • TMPRSS6

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)

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    de Falco, L., Silvestri, L., Kannengiesser, C., Morán, E., Oudin, C., Rausa, M., Bruno, M., Aranda, J., Argiles, B., Yenicesu, I., Falcon-Rodriguez, M., Yilmaz-Keskin, E., Kocak, U., Beaumont, C., Camaschella, C., Iolascon, A., Grandchamp, B., & Sanchez, M. (2014). Functional and clinical impact of novel Tmprss6 variants in iron-refractory iron-deficiency Anemia patients and genotype-phenotype studies. Human Mutation, 35(11), 1321-1329. https://doi.org/10.1002/humu.22632