Functional and clinical impact of novel tmprss6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies
| Autor: | Achille Iolascon, Idil Yenicesu, Maria Falcon-Rodriguez, Claire Oudin, Caroline Kannengiesser, Ülker Koçak, Bienvenida Argiles, Erica Moran, Jessica Aranda, Mariasole Bruno, Clara Camaschella, Ebru Yilmaz-Keskin, Laura Silvestri, Carole Beaumont, Bernard Grandchamp, Marco Rausa, Luigia De Falco, Mayka Sanchez |
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| Přispěvatelé: | Luigia De, Falco, Laura, Silvestri, Caroline, Kannengiesser, Erica, Moràn, Claire, Oudin, Marco, Rausa, Mariasole, Bruno, Jessica, Aranda, Bienvenida, Argile, Idil, Yenicesu, Maria Falcon, Rodriguez, Ebru Yilmaz, Keskin, Ulker, Kocak, Carole, Beaumont, Clara, Camaschella, Iolascon, Achille, Bernard, Grandchamp, Mayka, Sanchez, DE FALCO, L, Silvestri, L, Kannengiesser, C, Moran, E, Oudin, C, Rausa, M, Bruno, M, Aranda, J, Argiles, B, Yenicesu, I, FALCON RODRIGUEZ, M, YILMAZ KESKIN, E, Kocak, U, Beaumont, C, Camaschella, Clara, Iolascon, A, Grandchamp, B, Sanchez, M. |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male TMPRSS6 Adolescent Genotype Anemia Nonsense mutation IRIDA Young Adult iron deficiency Gene Frequency Hepcidin Gene Order Genetics medicine Humans Missense mutation Child Genetic Association Studies Genetics (clinical) Anemia Iron-Deficiency biology Transferrin saturation Microcytosis Serine Endopeptidases Genetic Variation Infant Membrane Proteins medicine.disease Hypochromic microcytic anemia genotype-phenotype Phenotype Genetic Loci Child Preschool Mutation Cancer research biology.protein iron-refractory anemia functional studies Female |
| Zdroj: | HUMAN MUTATION r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| ISSN: | 1059-7794 |
| Popis: | 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 proteasematriptase-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. (C) 2014 Wiley Periodicals, Inc. |
| Databáze: | OpenAIRE |
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