Thioredoxin Reductase 2 (TXNRD2) Mutation Associated With Familial Glucocorticoid Deficiency (FGD)

Abstract

Context:Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis.Objective:We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD.Design:Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis.Setting:The study was conducted on patients from three pediatric centers in the United Kingdom.Patients:Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study.Interventions:There were no interventions.Main Outcome Measure:Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured.Results:A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line.Conclusion:In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

“…Nevertheless, TXNRD2 is in the same pathway of ROS detoxification and TXNRD2 heterozygous mutations in humans have also been linked to dilated cardiomyopathy. Thus, for now, cardiac follow-up should be done (10,36).…”

“…Until 2012, only a half of FGD cases could be explained by homozygous or compound heterozygous mutations in genes involved in the steroidogenic pathway: MC2R (25%), MRAP (20%), STAR (5%), and more rarely CYP11A1 (3,4,5,6,7). Over the last 3 years, thanks to whole exome sequencing, three more causative genes have been discovered: mini chromosome maintenance deficient 4 homolog (MCM4), nicotinamide nucleotide transhydrogenase (NNT) and thioredoxin reductase 2 (TXNRD2) (8,9,10).…”

Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]

“…Gene mutations that have recently been shown to cause FGD include abnormalities of the gene that encodes the mitochondrial enzyme NNT (nicotinamide nucleotide transhydrogenase) and the gene that encodes thioredoxin reductase 2 (TXNRD2). Given that NTT and TXNRD2 act as an anti-oxidation system in mitochondria, the importance of mitochondrial redox control in steroidogenesis has been clarified [39,40].…”

Novel Insight into Etiology, Diagnosis and Management of Primary Adrenal Insufficiency

“…RT-PCR showed ubiquitous expression of the TXNRD2 gene in human tissues with high expression in the adrenal cortex [41]. TXNRD2 knockdown in adrenocortical NCI-H295R cells revealed increased production of ROS and susceptibility to oxidative stress.…”