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Functional and Clinical Impact of Novel Tmprss6 Variants in Iron‐Refractory Iron‐Deficiency Anemia Patients and Genotype–Phenotype Studies
Author(s) -
Falco Luigia,
Silvestri Laura,
Kannengiesser Caroline,
Morán Erica,
Oudin Claire,
Rausa Marco,
Bruno Mariasole,
Aranda Jessica,
Argiles Bienvenida,
Yenicesu Idil,
FalconRodriguez Maria,
YilmazKeskin Ebru,
Kocak Ulker,
Beaumont Carole,
Camaschella Clara,
Iolascon Achille,
Grandchamp Bernard,
Sanchez Mayka
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22632
Subject(s) - tmprss6 , hepcidin , biology , microcytosis , missense mutation , microcytic anemia , genotype , genetics , anemia , phenotype , iron deficiency , gene , medicine , serine protease , immunology , protease , biochemistry , inflammation , enzyme , hemoglobin
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.