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Cited by 439Adrenal Hormones and DisordersStress Responses and CortisolMetabolism and Genetic Disorders

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, David, Alessia, Becker, Christian, Rüschendorf, Franz, Naville, Danielle, Begeot, Martine +5 more·2005·Nature Genetics
DOI 10.1038/ng1501
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Abstract

Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to adrenocorticotropin (ACTH; OMIM 202200), is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood. Mutations of the ACTH receptor (melanocortin 2 receptor, MC2R) account for approximately 25% of cases of FGD. FGD without mutations of MC2R is called FGD type 2. Using SNP array genotyping, we mapped a locus involved in FGD type 2 to chromosome 21q22.1. We identified mutations in a gene encoding a 19-kDa single-transmembrane domain protein, now known as melanocortin 2 receptor accessory protein (MRAP). We show that MRAP interacts with MC2R and may have a role in the trafficking of MC2R from the endoplasmic reticulum to the cell surface.

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Crossref · 10.1038/ng1501

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  • MC2R is absolutely dependent on MRAP for cell surface expression and function.

    “The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function.”

    From ACTH Antagonists (2016) · cites this paper as [34]

  • FGD2, clinically indistinguishable from FGD1, is caused by mutations in the gene for melanocortin 2 receptor accessory protein (MRAP).

    “FGD2, which is clinically indistinguishable from FGD1, is caused by mutations in the gene for melanocortin 2 receptor accessory protein (MRAP) (119, 625, 626).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [625]

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Authors
Metherell, L. A., Chapple, J. P., Cooray, S., David, A., Becker, C., Rüschendorf, F., Naville, D., Begeot, M., Khoo, B., Nürnberg, P., Huebner, A., Cheetham, M. E., & Clark, A. J. L.
Affiliations
  • Queen Mary University of London (GB)
  • University College London (GB)
  • Max Delbrück Center (DE)
  • Inserm (FR)
  • Technische Universität Dresden (DE)
Corresponding author
Clark, Adrian J L
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2005-01-16
Volume
37
Issue
2
Pages
166-170
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng1501
OpenAlex
W2098925719
Semantic Scholar
b2d12120a324b7d71199b9cf119c7a50f2a35776
Cited by
437
References
28
Citations by year
2026: 5 · 2025: 9 · 2024: 12 · 2023: 22 · 2022: 26 · 2021: 36 · 2020: 12 · 2019: 18 · 2018: 19 · 2017: 26 · 2016: 22 · 2015: 22 · 2014: 33 · 2013: 25 · 2012: 22
FWCI
10.76
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
MRAP, melanocortin 2 receptor, ACTH receptor, receptor trafficking, endoplasmic reticulum, autosomal recessive disorder, adrenal cortex, cortisol deficiency, protein-protein interaction
MeSH terms
Adrenocorticotropic Hormone, Animals, Chromosome Mapping, Chromosomes, Human, Pair 21, Cricetulus, Female, Cricetinae, Humans, Male, Membrane Proteins, Molecular Sequence Data, Mutation, Pedigree, CHO Cells, Reverse Transcriptase Polymerase Chain Reaction, Receptor, Melanocortin, Type 2

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