Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2

Metherell, Louise A.; Chapple, J. Paul; Cooray, Sadani N.; David, Alessia; Becker, Christian; Rüschendorf, Franz; Naville, Danielle; Bégeot, Martine; Khoo, Bernard; Nürnberg, Peter; Huebner, Angela; Cheetham, Michael E.; Clark, Adrian

doi:10.1038/ng1501

Cited by 394 publications

(388 citation statements)

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“…The MC2 receptor is also unusual in its requirement for an accessory protein, the MC2 receptor accessory protein (MRAP) (2). MRAP must be expressed with the MC2 receptor in order for the receptor to undergo glycosylation, traffic to the plasma membrane, bind ACTH, and stimulate adenylyl cyclase (2)(3)(4).…”

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confidence: 99%

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Opposite Effects of the Melanocortin-2 (MC2) Receptor Accessory Protein MRAP on MC2 and MC5 Receptor Dimerization and Trafficking

Sebag

Hinkle

2009

Journal of Biological Chemistry

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MC2 (ACTH) receptors require MC2 receptor accessory protein (MRAP) to reach the cell surface. In this study, we show that MRAP has the opposite effect on the closely related MC5 receptor. In enzyme-linked immunosorbent assay and microscopy experiments, MC2 receptor was retained in the endoplasmic reticulum in the absence of MRAP and targeted to the plasma membrane with MRAP. MC5 receptor was at the plasma membrane in the absence of MRAP, but trapped intracellularly when expressed with MRAP. Using bimolecular fluorescence complementation, where one fragment of yellow fluorescent protein (YFP) was fused to receptors and another to MRAP, we showed that MC2 receptor-MRAP dimers were present at the plasma membrane, whereas MC5 receptor-MRAP dimers were intracellular. Both MC2 and MC5 receptors co-precipitated with MRAP. MRAP did not alter expression of ␤2-adrenergic receptors or co-precipitate with them. To determine if MRAP affects formation of receptor oligomers, we co-expressed MC2 receptors fused to YFP fragments in the presence or absence of MRAP. YFP fluorescence, reporting MC2 receptor homodimers, was readily detectable with or without MRAP. In contrast, MC5 receptor homodimers were visible in the absence of MRAP, but little fluorescence was observed by microscopic analysis when MRAP was co-expressed. Co-precipitation of differentially tagged receptors confirmed that MRAP blocks MC5 receptor dimerization. The regions of MRAP required for its effects on MC2 and MC5 receptors differed. These results establish that MRAP forms stable complexes with two different melanocortin receptors, facilitating surface expression of MC2 receptor but disrupting dimerization and surface localization of MC5 receptor.In mammals, the five members of the melanocortin (MC 2 ) receptor family play diverse physiological roles. MC1 receptors (melanocyte-stimulating hormone receptors) control pigmentation in many animals, MC2 receptors (ACTH receptors) regulate adrenal corticosteroid synthesis, MC3 and MC4 receptors in brain influence food intake and energy expenditure, and MC5 receptors control exocrine gland secretion (1). Melanocortin receptors (MC1 through MC5) are structurally related G protein-coupled receptors that respond to agonists with an increase in cAMP. The receptors differ in their affinity for physiological agonists (␣-, ␤-, and ␥-melanocyte-stimulating hormone and ACTH) and antagonists (agouti and agouti-related protein).Unlike other melanocortin receptors, MC2 receptors are selectively regulated by ACTH. The MC2 receptor is also unusual in its requirement for an accessory protein, the MC2 receptor accessory protein (MRAP) (2). MRAP must be expressed with the MC2 receptor in order for the receptor to undergo glycosylation, traffic to the plasma membrane, bind ACTH, and stimulate adenylyl cyclase (2-4). Individuals with inactivating mutations of either the MC2 receptor or MRAP suffer from ACTH resistance and severe glucocorticoid deficiency (2).MRAP is a small protein with a conserved amino terminus, single membrane-spann...

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confidence: 99%

“…MRAP must be expressed with the MC2 receptor in order for the receptor to undergo glycosylation, traffic to the plasma membrane, bind ACTH, and stimulate adenylyl cyclase (2)(3)(4). Individuals with inactivating mutations of either the MC2 receptor or MRAP suffer from ACTH resistance and severe glucocorticoid deficiency (2).…”

mentioning

confidence: 99%

Opposite Effects of the Melanocortin-2 (MC2) Receptor Accessory Protein MRAP on MC2 and MC5 Receptor Dimerization and Trafficking

Sebag

Hinkle

2009

Journal of Biological Chemistry

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“…Numerous disease genes have been localized using SNP-based genome-wide scans including genes implicated in multiple sclerosis (Sawcer et al, 2004(Sawcer et al, , 2005, Pelizaeus-Merzbacher-like disease (Uhlenberg et al, 2004), childhood severe retinal dystrophy (Janecke et al, 2004), neonatal diabetes (Sellick et al, 2003), age-related maculopathy (Jakobsdottir et al, 2005), erythrokeratodermia (Saba et al, 2005), arthrogryposisrenal dysfunction-cholestasis (ARC) syndrome (Gissen et al, 2004), familial glucocorticoid deficiency type 2 (Metherell et al, 2005), bipolar disorder , Charcot-Marie-Tooth disease (Shrimpton et al, 2004) and sudden infant death with dysgenesis of the testes (Puffenberger et al, 2004). Owing to the sporadic nature of cancer development, few linkage studies have been performed using SNP-based approaches.…”

Section: Linkage Studiesmentioning

confidence: 99%

Using high-throughput SNP technologies to study cancer

Engle¹,

2006

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Identifying genes involved in the development of cancer is crucial to fully understanding cancer biology, for developing novel therapeutics for cancer treatment and for providing methods for cancer prevention and early diagnosis. The use of polymorphic markers, in particular single nucleotide polymorphisms (SNPs), promises to provide a comprehensive tool for analysing the human genome and identifying those genes and genomic regions contributing to the cancer phenotype. This review summarizes the various analytical methodologies in which SNPs are used and presents examples of how each of these methodologies have been used to locate genes and genomic regions of interest for various cancer types. Additionally many of the current SNP-analysing technologies will be reviewed with particular attention paid to the advantages and disadvantages of each and how each technology can be applied to the analysis of the genome for identifying cancer-related genes.

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“…The functional expression of MC2R requires the MC2R accessory protein (MRAP), a protein involved in the trafficking of MC2R (2,3). Mutations in MC2R or MRAP cause familial glucocorticoid deficiency (FGD).…”

Section: Introductionmentioning

confidence: 99%

A corticotroph pituitary adenoma as the initial presentation of familial glucocorticoid deficiency

Benoit

Drui²,

Chaillous³

et al. 2009

European Journal of Endocrinology

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Context: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive ACTH-resistance syndrome characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Here, we report the case of a young woman with a corticotroph pituitary adenoma as the initial presentation of FGD. Case report: A 15-year-old girl was referred to our institution for a 16 mm pituitary adenoma associated with glucocorticoid deficiency. Clinical and biological features were evocative of FGD. DNA sequencing did not identify mutations in either the melanocortin 2 receptor (MC2R) or the MC2R accessory protein genes, indicating type 3 FGD. Despite adequate glucocorticoid replacement, plasma ACTH levels remained increased and pituitary magnetic resonance imaging (MRI) showed a progression of the tumour size resulting in optic chiasm compression with intra-tumoural haemorrhaging. When the patient was 26 years old, it was decided that she would undergo transsphenoidal surgery. The histomorphological analysis identified a well-individualized pituitary adenoma immunoreactive for ACTH. The proband's sister also exhibited type 3 FGD associated with pituitary hyperplasia upon MRI. Conclusion: This case highlights the relationship between FGD and hyperplasia of ACTH-producing cells, potentially leading to histologically proven pituitary corticotroph adenomas. This observation raises the question of the pituitary MRI's significance in the follow-up of FGD.

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Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2

Cited by 394 publications

References 23 publications

Opposite Effects of the Melanocortin-2 (MC2) Receptor Accessory Protein MRAP on MC2 and MC5 Receptor Dimerization and Trafficking

Opposite Effects of the Melanocortin-2 (MC2) Receptor Accessory Protein MRAP on MC2 and MC5 Receptor Dimerization and Trafficking

Using high-throughput SNP technologies to study cancer

A corticotroph pituitary adenoma as the initial presentation of familial glucocorticoid deficiency

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