title: Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2.
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.
authors.affiliation: Department of Endocrinology, William Harvey Research Institute, Barts & the London, Queen Mary, University of London, West Smithfield, London EC1A 7BE, UK.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
authors.forename: J Paul
authors.initials: JP
authors.lastname: Chapple
authors.forename: Sadani
authors.initials: S
authors.lastname: Cooray
authors.forename: Alessia
authors.initials: A
authors.lastname: David
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Danielle
authors.initials: D
authors.lastname: Naville
authors.forename: Martine
authors.initials: M
authors.lastname: Begeot
authors.forename: Bernard
authors.initials: B
authors.lastname: Khoo
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000172:deficiency*; D000818:Animals; D016466:CHO Cells; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C458099:MRAP protein, human; D008565:Membrane Proteins; D044103:Receptor, Melanocortin, Type 2; D000324:Adrenocorticotropic Hormone