Familial glucocorticoid deficiency: New genes and mechanisms

Meimaridou, Eirini; Hughes, Claire; Kowalczyk, Julia; Guasti, Leonardo; Chapple, J. Paul; King, Peter; Chan, Li F.; Clark, Adrian; Metherell, Louise A.

doi:10.1016/j.mce.2012.12.010

Cited by 73 publications

(85 citation statements)

References 32 publications

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“…Mutations in the MC2R gene are responsible for 25% of familial glucocorticoid deficiency (FGD) and mutations in the MRAP gene, encoding the MC2R accessory protein MRAP, are responsible for 20% of FGD (Meimaridou et al 2013, Jackson et al 2015. FGD is an autosomal recessive disorder resulting in cortisol deficiency, due to resistance of the adrenal cortex to the action of ACTH.…”

Section: Pathological Consequences Of Mc2r Deficiency For the Adrenalmentioning

confidence: 99%

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60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Gallo‐Payet

2016

Journal of Molecular Endocrinology

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The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo–pituitary–adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH.

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Section: Pathological Consequences Of Mc2r Deficiency For the Adrenalmentioning

confidence: 99%

“…After the discovery of the causative role of MRAP1 in FDG, more recent studies also identified another protein from the same family, MRAP2, which seems to be linked to obesity (Meimaridou et al 2013, Jackson et al 2015. Finally, it is important to consider extrapituitary production of ACTH.…”

Section: Adrenocortical Pathologies Associated With Defective Signalimentioning

confidence: 99%

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Gallo‐Payet

2016

Journal of Molecular Endocrinology

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“…In addition, patients suffer from failure to thrive, hypoglycemia, severe infections and fatigue. To date, the underlying genetic disorder is known in approximately 70% of patients with FGD [28]. The most common type is caused by a defect in the ACTH receptor MC2R, which is a 7-membrane G-protein coupled receptor located (almost) exclusively in the adrenocortical cells [29].…”

Section: Causes Of Paimentioning

confidence: 99%

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

Malíková¹,

Flück

2014

Horm Res Paediatr

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Primary adrenal insufficiency (PAI) is a rare condition in childhood which is either inherited (mostly) or acquired. It is characterized by glucocorticoid and maybe mineralocorticoid deficiency. The most common form in children is 21-hydroxylase deficiency, which belongs to the steroid biosynthetic defects causing PAI. Newer forms of complex defects of steroid biosynthesis are P450 oxidoreductase deficiency and (apparent) cortisone reductase deficiency. Other forms of PAI include metabolic disorders, autoimmune disorders and adrenal dysgenesis, e.g. the IMAGe syndrome, for which the underlying genetic defect has been recently identified. Newer work has also expanded the genetic causes underlying isolated, familial glucocorticoid deficiency (FGD). Mild mutations of CYP11A1 or StAR have been identified in patients with FGD. MCM4 mutations were found in a variant of FGD in an Irish travelling community manifesting with PAI, short stature, microcephaly and recurrent infections. Finally, mutations in genes involved in the detoxification of reactive oxygen species were identified in patients with unsolved FGD. Most mutations were found in the enzyme nicotinamide nucleotide transhydrogenase, which uses the mitochondrial proton pump gradient to produce NADPH. NADPH is essential in maintaining high levels of reduced forms of antioxidant enzymes for the reduction of hydrogen peroxide. Similarly, mutations in the gene for TXNRD2 involved in this system were found in FGD patients, suggesting that the adrenal cortex is particularly susceptible to oxidative stress.

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“…Since the mutations in MC2R, MRAP, and STAR have been found in ca. 50% of patients with FGD, and the mutation of MCM4 is extremely rare [1], it is inferred that NNT mutations account for 5-10% of FGD patients, and that underlying factor(s) still remain to be clarified in a substantial fraction of FGD patients.…”

Section: Disclosure Summarymentioning

confidence: 99%