Clinical and biological phenotype of a patient with familial glucocorticoid deficiency type 2 caused by a mutation of melanocortin 2 receptor accessory protein

Rumie, Hana; Metherell, Louise A.; Clark, Adrian; Beauloye, Véronique; Maes, Michaël

doi:10.1530/eje-07-0242

Cited by 21 publications

(14 citation statements)

References 13 publications

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“…This is probably consistent with the short stature of his parents. Early onset obesity has also been reported in one family with MRAP mutation (16), this is not a feature noted in our patient.…”

Section: Discussionsupporting

confidence: 71%

Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein

Jain

Metherell

David

et al. 2011

European Journal of Endocrinology

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BackgroundFamilial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency. Mutations in the ACTH receptor/melanocortin 2 receptor (MC2R), the MC2R accessory protein (MRAP) or the STAR protein (STAR) cause FGD types 1, 2 and 3, respectively, accounting for ∼50% of all cases.Patient and methodsWe report a neonate of Indian origin, who was diagnosed with FGD in the first few days of life. He presented with hypoglycaemic seizures and was noted to have generalised intense hyperpigmentation and normal male genitalia. Biochemical investigations revealed hypocortisolaemia (cortisol 0.223 μg/dl; NR 1–23 μg/dl) and elevated plasma ACTH (170 pg/ml). Serum electrolytes, aldosterone and plasma renin activity were normal. Peak cortisol following a standard synacthen test was 0.018 μg/dl. He responded to hydrocortisone treatment and continues on replacement. Patient DNA was analysed by direct sequencing. The effect of the novel mutation was assessed by an in vitro splicing assay using wild type and mutant heterologous minigenes.ResultsA novel homozygous mutation c.106+2_3dupTA was found in the MRAP gene. Both parents were heterozygous for the mutation. In an in vitro splicing assay, the mutation resulted in the skipping of exon 3.ConclusionWe have identified a novel MRAP mutation where disruption of the intron 3 splice-site results in a prematurely terminated translation product. This protein (if produced) would lack the transmembrane domain that is essential for MC2R interaction. We predict that this would cause complete lack of ACTH response thus explaining the early presentation in this case.

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Section: Discussionsupporting

confidence: 71%

Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein

Jain

Metherell

David

et al. 2011

European Journal of Endocrinology

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“…As an essential component for MC2R function, MRAP was first identified by Clark and colleagues in 2004 (Metherell et al 2004). Its mutation has been shown to be responsible for some cases of familial glucocorticoid deficiency type 2, in which there is elevated ACTH but low or absent circulating cortisol (Metherell et al 2005; Rumie et al 2007). By stimulating expression of both MC2R and MRAP concomitantly, ACTH forms a feed forward loop leading to amplification of responsiveness.…”

Section: Discussionmentioning

confidence: 99%

ACTH is a potent regulator of gene expression in human adrenal cells

Xing

Parker

Edwards

et al. 2010

Journal of Molecular Endocrinology

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The adrenal glands are the primary source of minerocorticoids, glucocorticoids and the so-called adrenal androgens. Under physiological conditions cortisol and adrenal androgen synthesis are controlled primarily by adrenocorticotrophic hormone (ACTH). Although it has been established that ACTH can stimulate steroidogenesis, the effects of ACTH on overall gene expression in human adrenal cells have not been established. In this study, we defined the effects of chronic ACTH treatment on global gene expression in primary cultures of both adult adrenal (AA) and fetal adrenal (FA) cells. Microarray analysis indicated that 48 h of ACTH treatment caused 30 AA genes and 84 AA genes to increase by greater than 4-fold, with 20 genes common in both cell cultures. Among these genes were six encoding enzymes involved in steroid biosynthesis, the ACTH receptor and its accessory protein, MRAP (ACTH receptor accessory protein). These data provide a group of ACTH-regulated genes including many that have not previously been studied with regard to adrenal function. These genes represent candidates for regulation of adrenal differentiation and steroid hormone biosynthesis.

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“…Although both MRAPs reduce MC3R signalling, it is more likely that MRAP2 regulates MC3R in vivo as both are mostly expressed in the hypothalamus. With the exception of one family, altered body weight has not been observed in patients with MRAP mutations, suggesting that MRAP may not be the key hypothalamic player (Rumie et al 2007). However, this does not exclude the possibility of MC3R regulation by MRAP in other tissues where MC3R is also expressed such as in adipose tissue, heart (Chagnon et al 1997), skeletal muscle, kidney (Chhajlani 1996), stomach, duodenum, placenta, pancreas (Gantz et al 1993) and immunocompetent cells (Getting et al 1999, Lindberg et al 2005.…”

Section: Mrap and Mrap2 Function Beyond The Adrenal Glandmentioning

confidence: 99%

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

Novoselova

Jackson

Campbell

et al. 2013

Journal of Endocrinology

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The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R-MC5R) with diverse physiological roles. MC1R controls pigmentation, MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency, where inactivating MRAP mutations account for w20% of cases. MRAP is highly expressed in both the zona fasciculata and the undifferentiated zone. Expression in the undifferentiated zone suggests that MRAP could also be important in adrenal cell differentiation and/or maintenance. In contrast, the role of adrenal MRAP2, which is highly expressed in the foetal gland, is unclear. The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R-mediated adrenal steroidogenesis. In vitro, MRAPs have been shown to reduce surface expression and signalling of all the other MCRs (MC1,3,4,5R). MRAP2 is predominantly expressed in the hypothalamus, a site that also expresses a high level of MC3R and MC4R. This raises the intriguing possibility of a CNS role for the MRAPs. Hypothalamic-pituitary-adrenal axisThe adrenal glands are responsible for releasing different classes of hormones. The inner part of the glands, the medulla, secretes catecholamines under the control of the sympathetic nervous system. The outer part, the cortex, has three functionally distinct layers -the outer zona glomerulosa that secretes aldosterone, the middle zona fasciculata that produces glucocorticoids and the inner zona reticularis that is responsible for the production of adrenal androgens. Production and release of glucocorticoids by the zona fasciculata are tightly regulated by the hypothalamus and pituitary to control

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Clinical and biological phenotype of a patient with familial glucocorticoid deficiency type 2 caused by a mutation of melanocortin 2 receptor accessory protein

Cited by 21 publications

References 13 publications

Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein

Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein

ACTH is a potent regulator of gene expression in human adrenal cells

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

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