Molecular Genetics of Inherited Glucocorticoid Deficiency

Abstract

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency and resistance of the adrenal cortex to adrenocorticotropic hormone (ACTH) action. Technological advances in genetics have contributed to our better understanding of the disease. Deoxyribonucleic acid (DNA) sequencing technology has given insight into the genetic cause of more than 60% of FGD cases, and revealed intersecting phenotypes with other adrenal insufficiency disorders. Defects have been recognised in the ACTH receptor (MC2R) and its accessory protein (MRAP), in the mitochondrial cholesterol transfer protein STAR, in MCM4 essential for DNA stability and repair and in NNT and TXNRD2, essential for redox homoeostasis/detoxification of ROS. The remaining causes are yet to be elucidated and using next generation sequencing tools could incriminate additional pathways responsible for the onset of the disease.

Key Concepts:

  • Glucocorticoid deficiency is a feature of many adrenal disorders with overlapping clinical presentations.

  • In most adrenal insufficiency disorders glucocorticoid deficiency is accompanied by mineralocorticoid deficiency.

  • Technological advances in genetics have accelerated our understanding of the genetic causes of such diseases.

  • Defects in novel pathways including those responsible for DNA stability and repair and those essential for redox homoeostasis/detoxification of ROS have recently been implicated in the pathogenesis of glucocorticoid deficiency.

  • 40% of isolated glucocorticoid deficiency remains of unknown aetiology.

Keywords: adrenal insufficiency; familial glucocorticoid deficiency; oxidative stress; Triple A syndrome; mutation

Figure 1.

NNT supplies NADPH for glutathione and thioredoxin antioxidant systems. MnSOD converts O2 into H2O2 and protects ROS‐sensitive proteins from oxidative damage. H2O2 is then removed by glutathione peroxidases (e.g. GPX1) or peroxiredoxins (e.g. PRDX3) using GSH and Trx(SH)2 as cofactors. GSH and Trx(SH)2 can be regenerated by glutathione reductase (GR) and thioredoxin reductase 2 (TXNRD2), respectively, using the reducing power from NADPH. NNT plays an important role in NADPH generation in the mitochondria. The transhydrogenase activity of NNT catalyses the interconversion of NADH and NADPH with the generation of NADPH as the predominant direction. Without NNT, the production of NADPH is compromised, causing the mitochondria to become more sensitive to oxidative stress.

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Further Reading

Maghnie M, Loche S, Cappa M, Ghizzoni L and Lorini R (eds) (2013) Hormone Resistance and Hypersensitivity, vol. 24. Karger. doi:10.1159/000342504.

Napier C and Pearce SH (2012) Autoimmune Addison's disease. La Presse Médicale 41(12P 2): e626–e635. doi:10.1016/j.lpm.2012.09.010.

Yates R, Katugampola H, Cavlan D et al. (2013) Adrenocortical development, maintenance, and disease. In: Thomas P (ed.) Current Topics in Developmental Biology, vol. 106, pp. 239–312. Burlington, VT: Academic Press. ISBN: 978‐0‐12–416021‐7.

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Meimaridou, Eirini, Kowalczyk, Julia, and Metherell, Louise A(Oct 2014) Molecular Genetics of Inherited Glucocorticoid Deficiency. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025368]