{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMRAP (melanocortin 2 receptor accessory protein) is a critical regulator of adrenal function. It was first identified in patients with familial glucocorticoid deficiency (FGD), where loss‐of‐function mutations in the MRAP gene result in ACTH resistance and isolated cortisol deficiency. These genetic findings establish that MRAP is indispensable for proper ACTH receptor (MC2R) activity, as its disruption underlies FGD type 2 and contributes significantly to adrenal insufficiency observed in both pediatric and adult patient populations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMRAP facilitates the efficient trafficking of the MC2 receptor from the endoplasmic reticulum to the plasma membrane. Mechanistic studies have revealed that MRAP is a small single‐transmembrane protein that forms unusual, antiparallel homodimers with dual topology—displaying both its N- and C-termini on the extracellular surface. This unique structure is essential not only for MC2R surface localization but also for its ability to bind ACTH and subsequently trigger downstream signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role as a chaperone, MRAP mediates and fine-tunes receptor signaling. Studies have shown that, while MRAP is indispensable for MC2R’s response to ACTH leading to cAMP production and adrenal steroidogenesis, its homolog MRAP2 also interacts with multiple melanocortin receptor subtypes. In vitro evidence suggests that MRAP isoforms can differentially affect receptor surface expression and signal transduction—in some contexts enhancing ACTH receptor coupling and, in others, modulating the responsiveness of receptors involved in energy homeostasis. These findings indicate that MRAP (and its isoforms) functions as a bidirectional regulator of both receptor trafficking and signaling efficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its established function in adrenal steroidogenesis, MRAP plays a pivotal role in modulating intracellular signaling cascades. Its interaction with G proteins and facilitation of cAMP production are essential for ACTH-induced activation of PKA and downstream targets, including MAP kinase pathways. Moreover, recent work has extended the functional repertoire of MRAP to adipose tissue, where it modulates ACTH-induced lipolysis and metabolic energy balance, likely through its association with the stimulatory G protein (Gαs). Collectively, these studies underscore MRAP’s central role not only in endocrine regulation but also in broader physiological processes impacting energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Louise A Metherell, J Paul Chapple, Sadani Cooray, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1501"}], "href": "https://doi.org/10.1038/ng1501"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15654338"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15654338"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Teng-Teng L L Chung, Li F Chan, Louise A Metherell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Endocrinol (Oxf) (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2265.2009.03663.x"}], "href": "https://doi.org/10.1111/j.1365-2265.2009.03663.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19558534"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19558534"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "H Rumié, L A Metherell, A J L Clark, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical and biological phenotype of a patient with familial glucocorticoid deficiency type 2 caused by a mutation of melanocortin 2 receptor accessory protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Endocrinol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/EJE-07-0242"}], "href": "https://doi.org/10.1530/EJE-07-0242"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17893271"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17893271"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "C R Hughes, T T Chung, A M Habeb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2009-2731"}], "href": "https://doi.org/10.1210/jc.2009-2731"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20427498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20427498"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "V Jain, L A Metherell, A David, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Endocrinol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/EJE-11-0581"}], "href": "https://doi.org/10.1530/EJE-11-0581"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21951701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21951701"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "R P Dias, L F Chan, L A Metherell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Endocrinol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/EJE-09-0720"}], "href": "https://doi.org/10.1530/EJE-09-0720"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19903795"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19903795"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Julien A Sebag, Patricia M Hinkle "}, {"type": "b", "children": [{"type": "t", "text": "Melanocortin-2 receptor accessory protein MRAP forms antiparallel homodimers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0708916105"}], "href": "https://doi.org/10.1073/pnas.0708916105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18077336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18077336"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Julien A Sebag, Patricia M Hinkle "}, {"type": "b", "children": [{"type": "t", "text": "Regions of melanocortin 2 (MC2) receptor accessory protein necessary for dual topology and MC2 receptor trafficking and signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M804413200"}], "href": "https://doi.org/10.1074/jbc.M804413200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18981183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18981183"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Tom R Webb, Li Chan, Sadani N Cooray, et al. 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