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

Cecile Brachet; Alexander Laemmle; Martine Cools; Kay-Sara Sauter; Baere Elfride De; Arnaud Vanlander; Pandey Amit V.; Toit Therina du; Voegel Clarissa D.; Claudine Heinrichs; Hannah Verdin; Flück Christa E.

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ESPE Abstracts (2024) 98 FC8.3

ESPE2024 Free Communications Adrenals and HPA Axis 2 (6 abstracts)

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

Cecile Brachet ¹ , Alexander Laemmle ² , Martine Cools ³ , Kay-Sara Sauter ² , Elfride De Baere ⁴ , Arnaud Vanlander ⁵ , Amit V. Pandey ² , Therina du Toit ⁶ , Clarissa D. Voegel ⁷ , Claudine Heinrichs ¹ , Hannah Verdin ⁴ & Christa E. Flück ²

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Author affiliations

¹Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Paediatric Endocrinology Unit, Bruxelles, Belgium. ²Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. ³Department of Internal Medicine and Pediatrics, Ghent University; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital, Ghent, Belgium. ⁴Center for Medical Genetics, Ghent University Hospital; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. ⁵Mitochondrial Investigations Laboratory, Ghent University C. Heymanslaan 10, 9000 Gent, Ghent, Belgium and Department of Internal Medicine and Paediatrics, Ghent, Belgium. ⁶Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, Bern, Switzerland. ⁷Department of Biomedical Research, University of Bern, Bern, Switzerland

Objective: Adrenal cortisol production occurs through a biosynthetic pathway which depends 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, bi-allelic 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 FAD binding. Patient-derived iALC showed loss of cortisol production with overall diminished adrenal steroidogenesis, while ROS production was significantly increased.

Conclusion: This report illustrates the importance of the mitochondrial ROS detoxification system for steroidogenesis along with the phenotypic variability typical of mitochondrial dysfunction.