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Endocrine Abstracts (2013) 33 OC1.7 | DOI: 10.1530/endoabs.33.OC1.7

1William Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK; 2Inherited Cardiovascular Diseases Unit, Department of Cardiology, Great Ormond Street Hospital for Children, London, UK; 3Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK; 4Department of Paediatric Endocrinology, Luton and Dunstable University Hospital, Luton, UK.


Background: Novel pathogenic mechanisms involving replicative and oxidative stress have recently been described in familial glucocorticoid deficiency (FGD); including mutations in NNT. NNT supplies high concentrations of NADPH needed by the glutathione and thioredoxin anti-oxidant systems to detoxify mitochondrial H2O2.

Six patients, from a consanguineous Kashmiri family, were diagnosed with glucocorticoid deficiency between 0.1 and 10.8 years of age and were mutation negative for known causes of FGD.

Methods: Whole exome sequencing was performed on three affected individuals followed by Sanger sequencing of all family members. A TXNRD2-knockdown human adrenocortical H295R cell line was established to investigate redox homeostasis.

Results: A novel homozygous mutation, p.Y447X in TXNRD2 was identified segregating with disease in this kindred. TXNRD2 is a mitochondrial selenoprotein, dependent upon a c-terminal selenocysteine to maintain enzyme activity. TXNRD2 knockout is described as embryonic lethal in mice due to cardiac malformation and heterozygous mutations are described in humans with dilated cardiomyopathy. We find that TXNRD2 is ubiquitously expressed in human tissues with high mRNA levels in the adrenal cortex. The predicted consequence of the mutation was premature truncation removing the selenocysteine residue, however RT-PCR of patient cDNA and western blotting of patient lysates revealed complete absence of TXNRD2 in patients homozygous for the mutation presumably as a result of nonsense-mediated decay of mRNA. In our affected homozygote individuals, with apparent absence of TXNRD2, we observe no evidence of cardiomyopathy or conduction disease. TXNRD2-knockdown in the H295R cell line leads to increased oxidative stress with pressure on the glutathione system and increased mitochondrial superoxide production.

Conclusion: A delicate balance of mitochondrial redox regulation controls 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.

Volume 33

41st Meeting of the British Society for Paediatric Endocrinology and Diabetes

British Society for Paediatric Endocrinology and Diabetes 

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