title: Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies.
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.
authors.affiliation: CEINGE, Biotecnologie Avanzate, Naples, Italy.
authors.forename: Luigia
authors.initials: L
authors.lastname: De Falco
authors.forename: Laura
authors.initials: L
authors.lastname: Silvestri
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Erica
authors.initials: E
authors.lastname: Morán
authors.forename: Claire
authors.initials: C
authors.lastname: Oudin
authors.forename: Marco
authors.initials: M
authors.lastname: Rausa
authors.forename: Mariasole
authors.initials: M
authors.lastname: Bruno
authors.forename: Jessica
authors.initials: J
authors.lastname: Aranda
authors.forename: Bienvenida
authors.initials: B
authors.lastname: Argiles
authors.forename: Idil
authors.initials: I
authors.lastname: Yenicesu
authors.forename: Maria
authors.initials: M
authors.lastname: Falcon-Rodriguez
authors.forename: Ebru
authors.initials: E
authors.lastname: Yilmaz-Keskin
authors.forename: Ulker
authors.initials: U
authors.lastname: Kocak
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Mayka
authors.initials: M
authors.lastname: Sanchez
mesh_terms: D000293:Adolescent; D000328:Adult; D018798:Anemia, Iron-Deficiency / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D023061:Gene Order; D056726:Genetic Association Studies; D056426:Genetic Loci; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human
keywords: IRIDA; TMPRSS6; functional studies; genotype-phenotype; iron-refractory anemia