{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:05:30Z","timestamp":1780391130999,"version":"3.54.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,8,3]],"date-time":"2024-08-03T00:00:00Z","timestamp":1722643200000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004385","name":"Ghent University","doi-asserted-by":"publisher","award":["BOF\/STA\/202209\/040"],"award-info":[{"award-number":["BOF\/STA\/202209\/040"]}],"id":[{"id":"10.13039\/501100004385","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Adrenal cortisol production occurs through a biosynthetic pathway which depend on NADH and NADPH for energy supply. The mitochondrial respiratory chain and the reactive oxygen species (ROS) detoxification system are therefore important for steroidogenesis. Mitochondrial dysfunction leading to oxidative stress has been implicated in the pathogenesis of several adrenal conditions. Nonetheless, only very few patients with variants in one gene of the ROS detoxification system, Thioredoxin Reductase 2 (TXNRD2), have been described with variable phenotypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Clinical, genetic, structural, and functional characterization of a novel, biallelic TXNRD2 splice variant.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>On human biomaterial, we performed whole exome sequencing to identify and RNA analysis to characterize the specific TXNRD2 splice variant. Amino acid conservation analysis and protein structure modeling were performed in silico. Using patient's fibroblast-derived human induced pluripotent stem cells, we generated adrenal-like cells (iALC) to study the impact of wild-type (WT) and mutant TXNRD2 on adrenal steroidogenesis and ROS production.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The patient had a complex phenotype of primary adrenal insufficiency (PAI), combined with genital, ophthalmological, and neurological features. He carried a homozygous splice variant c.1348-1G &amp;gt; T in TXNRD2 which leads to a shorter protein lacking the C-terminus and thereby affecting homodimerization and flavin adenine dinucleotide binding. Patient-derived iALC showed a loss of cortisol production with overall diminished adrenal steroidogenesis, while ROS production was significantly increased.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ejendo\/lvae090","type":"journal-article","created":{"date-parts":[[2024,8,4]],"date-time":"2024-08-04T02:32:46Z","timestamp":1722738766000},"page":"144-155","source":"Crossref","is-referenced-by-count":4,"title":["Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous <i>TXNRD2<\/i> splice variant"],"prefix":"10.1093","volume":"191","author":[{"given":"C\u00e9cile","family":"Brachet","sequence":"first","affiliation":[{"name":"Universit\u00e9 libre de Bruxelles (ULB), H\u00f4pital Universitaire de Bruxelles (H.U.B), H\u00f4pital Universitaire des Enfants Reine Fabiola (HUDERF), Paediatric Endocrinology Unit , Avenue J.J. Crocq 15, 1020 Bruxelles , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Laemmle","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern , 3010 Bern , Switzerland"},{"name":"Department of Biomedical Research, University of Bern , 3010 Bern , Switzerland"},{"name":"Institute of Clinical Chemistry, University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-4899","authenticated-orcid":false,"given":"Martine","family":"Cools","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Pediatrics, Ghent University; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital , 9000 Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay-Sara","family":"Sauter","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern , 3010 Bern , Switzerland"},{"name":"Department of Biomedical Research, University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elfride","family":"De Baere","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, Ghent University Hospital; Department of Biomolecular Medicine, Ghent University , C. Heymanslaan 10, 9000 Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Vanlander","sequence":"additional","affiliation":[{"name":"Mitochondrial Investigations Laboratory, Ghent University C. Heymanslaan 10, 9000 Ghent, Ghent, Belgium and Department of Internal Medicine and Paediatrics, Ghent University Hospital , 9000 Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit V","family":"Pandey","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern , 3010 Bern , Switzerland"},{"name":"Department of Biomedical Research, University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Therina","family":"du Toit","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, University of Bern , 3010 Bern , Switzerland"},{"name":"Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa D","family":"Voegel","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, University of Bern , 3010 Bern , Switzerland"},{"name":"Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"Heinrichs","sequence":"additional","affiliation":[{"name":"Universit\u00e9 libre de Bruxelles (ULB), H\u00f4pital Universitaire de Bruxelles (H.U.B), H\u00f4pital Universitaire des Enfants Reine Fabiola (HUDERF), Paediatric Endocrinology Unit , Avenue J.J. 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