{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T23:02:59Z","timestamp":1789599779239,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Keros Therapeutics, Inc., Lexington"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic TMPRSS6 variant. Eight unaffected relatives with identical exonic TMPRSS6 variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT\/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic TMPRSS6-affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic TMPRSS6 variant.<\/jats:p>","DOI":"10.3390\/genes13081309","type":"journal-article","created":{"date-parts":[[2022,7,24]],"date-time":"2022-07-24T22:49:02Z","timestamp":1658702942000},"page":"1309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5036-8554","authenticated-orcid":false,"given":"Vera","family":"Hoving","sequence":"first","affiliation":[{"name":"Department of Hematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1768-7975","authenticated-orcid":false,"given":"Scott E.","family":"Korman","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petros","family":"Antonopoulos","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albertine E.","family":"Donker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, M\u00e1xima Medical Center, De Run 4600, 5504 NB Veldhoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia E. M.","family":"Schols","sequence":"additional","affiliation":[{"name":"Department of Hematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1040-9446","authenticated-orcid":false,"given":"Dorine W.","family":"Swinkels","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands"},{"name":"Sanquin Blood Bank, Sanquin Diagnostics BV, Plesmanlaan 125, 1066 NH Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.3324\/haematol.2012.075515","article-title":"Iron refractory iron deficiency anemia","volume":"98","author":"Sanchez","year":"2013","journal-title":"Haematologica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/ng.130","article-title":"Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)","volume":"40","author":"Finberg","year":"2008","journal-title":"Nat. Genet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E482","DOI":"10.1002\/ajh.24561","article-title":"Iron refractory iron deficiency anemia: A heterogeneous disease that is not always iron refractory","volume":"91","author":"Donker","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.1182\/blood-2014-01-548776","article-title":"Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis","volume":"123","author":"Donker","year":"2014","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/10245332.2017.1317990","article-title":"A child with severe iron-deficiency anemia and a complex TMPRSS6 genotype","volume":"22","author":"Capra","year":"2017","journal-title":"Hematology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/j.1365-2141.2012.09198.x","article-title":"Two novel mutations in the tmprss6 gene associated with iron-refractory iron-deficiency anaemia (irida) and partial expression in the heterozygous form","volume":"158","author":"Pellegrino","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/bjh.12147","article-title":"A novel mutation in the CUB sequence of matriptase-2 (TMPRSS6) is implicated in iron-resistant iron deficiency anaemia (IRIDA)","volume":"160","author":"Jaspers","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1559s","DOI":"10.3945\/ajcn.117.155804","article-title":"Current understanding of iron homeostasis","volume":"106","author":"Anderson","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1182\/blood-2017-05-786590","article-title":"Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin","volume":"131","author":"Aschemeyer","year":"2018","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1182\/blood-2018-01-824151","article-title":"How does hepcidin hinder ferroportin activity?","volume":"131","author":"Zhang","year":"2018","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nemeth, E., and Ganz, T. (2021). Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126493"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Vogt, A.S., Arsiwala, T., Mohsen, M., Vogel, M., Manolova, V., and Bachmann, M.F. (2021). On Iron Metabolism and Its Regulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094591"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1182\/blood-2015-12-639112","article-title":"Hepcidin in the diagnosis of iron disorders","volume":"127","author":"Girelli","year":"2016","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/bs.vh.2019.01.002","article-title":"Hepcidin-ferroportin axis in health and disease","volume":"110","author":"Ginzburg","year":"2019","journal-title":"Vitam. Horm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1097\/HS9.0000000000000035","article-title":"Erythroferrone: An Erythroid Regulator of Hepcidin and Iron Metabolism","volume":"2","author":"Coffey","year":"2018","journal-title":"Hemasphere"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1126\/science.1157121","article-title":"The serine protease TMPRSS6 is required to sense iron deficiency","volume":"320","author":"Du","year":"2008","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18354","DOI":"10.1074\/jbc.M117.801795","article-title":"Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway","volume":"292","author":"Wahedi","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/bs.vh.2019.01.004","article-title":"Hepcidin and the BMP-SMAD pathway: An unexpected liaison","volume":"110","author":"Silvestri","year":"2019","journal-title":"Vitam. Horm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1074\/jbc.RA118.006468","article-title":"The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin","volume":"294","author":"Mao","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1002\/humu.22116","article-title":"Inactive matriptase-2 mutants found in IRIDA patients still repress hepcidin in a transfection assay despite having lost their serine protease activity","volume":"33","author":"Guillem","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_21","first-page":"1321","article-title":"Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies","volume":"35","author":"Silvestri","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_22","first-page":"405","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_23","unstructured":"Wallis, Y., Payne, S., McAnulty, C., Bodmer, D., Sister-mans, E., Robertson, K., Moore, D., Abbs, S., Deans, Z., and Devereau, A. (2013). Practice Guidelines for the Evaluation of Pathogenicity and the Reporting of Sequence Variants in Clinical Molecular Genetics, Association for Clinical Genetic Science and the Dutch Society of Clinical Genetic Laboratory Specialists."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"van der Staaij, H., Donker, A.E., Bakkeren, D.L., Salemans, J., Mignot-Evers, L.A.A., Bongers, M.Y., Dieleman, J.P., Galesloot, T.E., Laarakkers, C.M., and Klaver, S.M. (2022). Transferrin Saturation\/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031917"},{"key":"ref_25","unstructured":"Hepcidinanalysis (2022, February 25). Reference Values WCX-TOF MS for Serum Hepcidin-25. Available online: http:\/\/www.hepcidinanalysis.com\/provided-service\/reference-values\/."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1515\/cclm-2018-0783","article-title":"Provisional standardization of hepcidin assays: Creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material","volume":"57","author":"Diepeveen","year":"2019","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1515\/cclm-2020-0928","article-title":"Optimizing hepcidin measurement with a proficiency test framework and standardization improvement","volume":"59","author":"Aune","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_28","unstructured":"Westgard, Q.C. (2022, April 22). Westgard Rules and Multirules. Available online: https:\/\/www.westgard.com\/mltirule.htm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S0091-679X(04)75032-3","article-title":"Detecting copy number changes in genomic DNA: MAPH and MLPA","volume":"75","author":"White","year":"2004","journal-title":"Methods Cell Biol."},{"key":"ref_30","unstructured":"Alamut Visual, I.B.T. (2022, April 22). Available online: https:\/\/www.interactive-biosoftware.com\/alamut-visual\/."},{"key":"ref_31","first-page":"704","article-title":"TMPRSS6 gene\u2014Two new nonsense mutations associated with IRIDA","volume":"95","author":"Palare","year":"2010","journal-title":"Haematologica"},{"key":"ref_32","first-page":"E236","article-title":"Allelic heterogeinity of TMPRSS6 mutations in IRIDA","volume":"84","author":"Kannengiesser","year":"2009","journal-title":"Am. J. Hematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.bcmd.2009.09.001","article-title":"Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia","volume":"44","author":"Beutler","year":"2010","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"151995","DOI":"10.1016\/j.imbio.2020.151995","article-title":"Estrogen signaling differentially alters iron metabolism in monocytes in an Interleukin 6-dependent manner","volume":"225","author":"Bajbouj","year":"2020","journal-title":"Immunobiology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1002\/hep.26648","article-title":"Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin","volume":"59","author":"Latour","year":"2014","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Li, Q., Wang, Y., Pan, Y., Wang, J., Yu, W., and Wang, X. (2021). Unraveling synonymous and deep intronic variants causing aberrant splicing in two genetically undiagnosed epilepsy families. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-01008-8"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Serre, D., Gurd, S., Ge, B., Sladek, R., Sinnett, D., Harmsen, E., Bibikova, M., Chudin, E., Barker, D.L., and Dickinson, T. (2008). Differential allelic expression in the human genome: A robust approach to identify genetic and epigenetic cis-acting mechanisms regulating gene expression. PLoS Genet., 4.","DOI":"10.1371\/journal.pgen.1000006"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1146\/annurev-biodatasci-021621-122219","article-title":"Perspectives on Allele-Specific Expression","volume":"4","author":"Cleary","year":"2021","journal-title":"Annu. Rev. Biomed. Data Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1080\/10715762.2020.1867314","article-title":"Recent advances in iron homeostasis and regulation\u2014A focus on epigenetic regulation and stroke","volume":"55","author":"Shi","year":"2021","journal-title":"Free Radic Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/s41467-017-00500-z","article-title":"Hepcidin is regulated by promoter-associated histone acetylation and HDAC3","volume":"8","author":"Pasricha","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.soard.2019.10.005","article-title":"DNA methylation suppresses liver Hamp expression in response to iron deficiency after bariatric surgery","volume":"16","author":"Huang","year":"2020","journal-title":"Surg. Obes. Relat. Dis."},{"key":"ref_42","first-page":"58","article-title":"Progress on epigenetic regulation of iron homeostasis","volume":"49","author":"Duan","year":"2020","journal-title":"Zhejiang Da Xue Xue Bao Yi Xue Ban"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"Claringbould","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s42003-020-01575-z","article-title":"A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis","volume":"4","author":"Bell","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1182\/blood-2017-03-773481","article-title":"A new form of IRIDA due to combined heterozygous mutations of TMPRSS6 and ACVR1A encoding the BMP receptor ALK2","volume":"129","author":"Pagani","year":"2017","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1182\/blood-2010-04-278655","article-title":"Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice","volume":"116","author":"Nai","year":"2010","journal-title":"Blood"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1309\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:55:16Z","timestamp":1760140516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,23]]},"references-count":46,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["genes13081309"],"URL":"https:\/\/doi.org\/10.3390\/genes13081309","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,23]]}}}