Brachet, Cécile; Laemmle, Alexander; Cools, Martine; Sauter, Kay-Sara; De Baere, Elfride; Vanlander, Arnaud; Pandey, Amit V; Du Toit, Therina; Voegel, Clarissa D; Heinrichs, Claudine; Verdin, Hannah; Flück, Christa E (2024). Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant. European journal of endocrinology, 191(2), pp. 144-155. Oxford Academic 10.1093/ejendo/lvae090
|
Text
lvae090.pdf - Accepted Version Available under License Creative Commons: Attribution (CC-BY). Download (1MB) | Preview |
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, 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
Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production.
Actions (login required)
 |
Edit item |