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Widening the Spectrum of TMPRSS6 Gene Pathogenic Variants Related with Hereditary Iron Deficiency

2021-11Documento de conferência Acesso aberto
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dc.contributor.authorPessoa, Vera
dc.contributor.authorOliveira, Alexandra
dc.contributor.authorSantos, Daniela
dc.contributor.authorMendonça, Joana
dc.contributor.authorMachado, Miguel P.
dc.contributor.authorFerrão, José
dc.contributor.authorVieira, Luís
dc.contributor.authorLopes, Pedro
dc.contributor.authorKislaya, Irina
dc.contributor.authorMatias-Dias, Carlos
dc.contributor.authorBarreto, Marta
dc.contributor.authorFaustino, Paula
dc.date.accessioned2022-02-22T16:37:18Z
dc.date.available2022-02-22T16:37:18Z
dc.date.issued2021-11
dc.description.abstractIron-Refractory Iron-Deficiency Anemia (IRIDA) is a rare autosomal recessive hypochromic microcytic anemia derived from loss-of-function mutations in the TMPRSS6 gene, which encodes Matriptase-2, a negative regulator of hepcidin expression. IRIDA patients have high hepcidin levels that prevent iron absorption and recycling. Very few studies concerning this pathology have been carried out in the Portuguese population and its molecular basis is still largely unknown. In this study, we aimed to identify genetic variants in TMPRSS6 in a sample of the Portuguese population with a hematological phenotype suggestive of iron deficiency. In addition, we intended to evaluate the performance of NGS for genetic screening of this large gene. We studied 100 adults with anemia and/or microcytosis and/or hypochromia collected by the Portuguese National Health Examination Survey (INSEF). Other possible genetic causes for these abnormal phenotypes, namely α- and β-thalassemia, were discarded after HBA1, HBA2 and HBB genetic screening. The TMPRSS6 gene (18 coding regions, exon/intron boundaries and regulatory regions) was amplified in 3 long-PCR fragments that were screened by NGS using Nextera XT libraries in a MiSeq platform. The genetic variants found were validated by Sanger sequencing (transcript ENST00000676104.1). Several known variants were identified along with two unreported mutations, c.1585T>C (p.Cys529Arg) and c.1580T>G (p.Phe527Cys). These novel mutations were classified as pathogenic by in silico analyses through Polyphen2, SIFT, and Missense3D. Moreover, Phyre2 software was used to produce a 3D structure of the mutated proteins, based on alignments with known protein structures, as there is no 3D model for Matriptase-2 on online databases. The two novel mutations were found in heterozygosity, explaining the mild abnormal hematological phenotypes and serum iron biomarkers presented by both patients. Functional studies should be performed to validate these findings. Our results widened the spectrum of TMPRSS6 pathogenic variants underlying hereditary iron deficiency-related pathologies. In addition, NGS revealed to be an appropriate tool for TMPRSS6 genetic screening.pt_PT
dc.description.sponsorshipEste trabalho é um sub-estudo do INSEF, desenvolvido no âmbito do Projeto Pré-definido do Programa Iniciativas em Saúde Pública, foi promovido pelo Instituto Nacional de Saúde Doutor Ricardo Jorge através do Departamento de Epidemiologia e beneficiou de apoio financeiro concedido pela Islândia, Liechtenstein e Noruega, através das EEA Grantspt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7964
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.subjectGene TMPRSS6pt_PT
dc.subjectAnemia Ferropénicapt_PT
dc.subjectModificadores Genéticospt_PT
dc.subjectMutaçõespt_PT
dc.subjectINSEFpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectFerropt_PT
dc.subjectIRIDApt_PT
dc.subjectMicrocitosept_PT
dc.subjectHipocromiapt_PT
dc.subjectDeterminantes da Saúde e da Doençapt_PT
dc.titleWidening the Spectrum of TMPRSS6 Gene Pathogenic Variants Related with Hereditary Iron Deficiencypt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlace(online)pt_PT
oaire.citation.title25th Annual Meeting of the Portuguese Society of Human Genetics, 18-19 Novembro 2021pt_PT
person.familyNameFaustino
person.givenNamePaula
person.identifier.ciencia-idF01A-353A-433E
person.identifier.orcid0000-0002-6269-4867
person.identifier.ridM-3519-2014
person.identifier.scopus-author-id8158641100
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT
relation.isAuthorOfPublication94303e78-8b7d-4e24-811d-3af3b1a4e330
relation.isAuthorOfPublication.latestForDiscovery94303e78-8b7d-4e24-811d-3af3b1a4e330

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