Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant.

Autor:	Brachet C; Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Paediatric Endocrinology Unit, Avenue J.J. Crocq 15, 1020 Bruxelles, Belgium., Laemmle A; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.; Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland.; Institute of Clinical Chemistry, University of Bern, 3010 Bern, Switzerland., Cools M; Department of Internal Medicine and Pediatrics, Ghent University; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium., Sauter KS; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.; Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland., De Baere E; Center for Medical Genetics, Ghent University Hospital; Department of Biomolecular Medicine, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium., Vanlander A; 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., Pandey AV; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.; Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland., du Toit T; Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland.; Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland., Voegel CD; Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland.; Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland., Heinrichs C; Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Paediatric Endocrinology Unit, Avenue J.J. Crocq 15, 1020 Bruxelles, Belgium., Verdin H; Center for Medical Genetics, Ghent University Hospital; Department of Biomolecular Medicine, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium., Flück CE; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.; Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2024 Aug 05; Vol. 191 (2), pp. 144-155.
DOI:	10.1093/ejendo/lvae090
Abstrakt:	Objective: 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. Design: Clinical, genetic, structural, and functional characterization of a novel, biallelic TXNRD2 splice variant. Methods: 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. Results: 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 > 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. Conclusion: Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production. Competing Interests: Conflict of interest: The authors have no conflict of interest to declare. (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)
Databáze:	MEDLINE
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