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Endocrine Abstracts (2013) 31 OC2.5 | DOI: 10.1530/endoabs.31.OC2.5

SFEBES2013 Oral Communications Steroids and thyroid (8 abstracts)

A mutation in thioredoxin reductase 2 (TXNRD2) is associated with a predominantly adrenal phenotype in humans

Rathi Prasad 1 , Claire Hughes 1 , Li Chan 1 , Catherine Peters 2 , Nisha Nathwani 3 , Adrian Clark 1 , Helen Storr 1 & Louise Metherell 1


1Barts and the London School of Medicine and Dentistry, QMUL, William Harvey Research Institute, Centre for Endocrinology, London, UK; 2Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 3Luton and Dunstable University Hospital, Luton, UK.


Familial glucocorticoid deficiency (FGD, OMIM#202200) is a rare autosomal recessive disorder characterised by adrenal resistance to the action of ACTH, with isolated glucocorticoid deficiency. Recently, mutations in NNT, encoding the mitochondrial anti-oxidant nicotinamide nucleotide transhydrogenase have been reported to cause FGD.

Our index case, from a highly consanguineous Kashmiri family, was diagnosed with adrenal insufficiency during a septic episode at the age of 12 years. Her sister was subsequently diagnosed at 4.5 years with a 2 years history of hyperpigmentation. Three of the index case’s children were diagnosed with FGD between the ages of 0.3–2.9 years on screening and their first cousin was diagnosed aged 0.1 year after presenting with poor feeding and heart failure secondary to a truncus arteriosis cardiac malformation.

Whole exome sequencing of three affected family members identified a novel homozygous mutation, Y447X in TXNRD2, encoding thioredoxin reductase 2 that segregated with the disease in this extended kindred. TXNRD2 is a predominantly mitochondrial selenoprotein, dependent upon a c-terminal selenocysteine residue for reduction of the active site disulphide in anti-oxidant thioredoxins and integral in maintaining thioredoxin activity. TXNRD2 knockout is embryonic lethal in mice due to cardiac malformation, cardiac specific ablation leads to dilated cardiomyopathy (DCM) and heterozygous mutations have also been described in humans with DCM. The mutation was predicted to lead to premature truncation and removal of the selenocysteine residue, however RT-PCR and western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation presumably as a result of nonsense-mediated decay of mRNA.

Previous studies describe a delicate balance of mitochondrial redox regulation controlling steroidogenesis at the level of the adrenal gland. We report the first mutation in TXNRD2 associated with a predominantly adrenal phenotype, indicating the importance of the thioredoxin system in maintaining redox homeostasis in the adrenocortical environment.

Declaration of funding

This work was supported by the Medical Research Council and the Wellcome Trust.

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