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

Nature Genetics volume 37, pages 166–170 (2005)Cite this article

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 childhood1,2,3. Mutations of the ACTH receptor (melanocortin 2 receptor, MC2R) account for ∼25% of cases of FGD4,5,6,7. 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 protein8, 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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Figure 1: Identification of MRAP.
Figure 2: Mutations of MRAP in individuals with FGD type 2.
Figure 3: Relative expression of MRAP-α (white bars), MRAP-β (black bars) and MC2R (gray bars) in human tissues analyzed by RT-PCR.
Figure 4: Colocalization of Mrap with Mc2r.
Figure 5: Mrap and Mc2r form a complex.
Figure 6: Mrap is required for Mc2r responsiveness in SK-N-SH cells.

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Acknowledgements

We thank M. Korbonits for supplying the human tissue RNA panel, S. Chew for advice and support for RNA splicing studies and G. Cooper for providing the Mrap-FLAG expression vector. This work was supported by a grant from the Biotechnology and Biological Sciences Research Council and the 2002 British Society of Paediatric Endocrinology and Diabetes prize awarded to L.A.M. and A.J.L.C. The work was further supported by the German Federal Ministry of Science and Education through the National Genome Research Network (C.B., F.R. and P.N.).

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Authors and Affiliations

  1. Department of Endocrinology, William Harvey Research Institute, Barts & the London, Queen Mary, University of London, West Smithfield, London, EC1A 7BE, UK

    Louise A Metherell, Sadani Cooray, Alessia David, Bernard Khoo & Adrian J L Clark

  2. Division of Pathology, Institute of Ophthalmology, University College London, London, EC1V 9EL, UK

    J Paul Chapple & Michael E Cheetham

  3. Molecular Genetics and Gene Mapping Center, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany

    Christian Becker, Franz Rüschendorf & Peter Nürnberg

  4. INSERM U 418, Hopital Debrousse, Lyon, 69322, France

    Danielle Naville & Martine Begeot

  5. Institute of Medical Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany

    Peter Nürnberg

  6. Children's Hospital, Technical University Dresden, Dresden, Germany

    Angela Huebner

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  1. Louise A Metherell
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Correspondence to Adrian J L Clark.

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Supplementary information

Supplementary Fig. 1

Analysis of tissue distribution of genes within the FGD2 critical region. (PDF 281 kb)

Supplementary Fig. 2

In vitro splicing assay demonstrating that mutation of the IVS3 donor splice site impair splicing. (PDF 199 kb)

Supplementary Fig. 3

Alignment of N-terminal region of human, mouse and rat MRAP orthologues and human C6orf117. (PDF 88 kb)

Supplementary Fig. 4

Intracellular mrap co-localized with ER markers. (PDF 92 kb)

Supplementary Table 1

Genes identified within the FGD2 critical region. (PDF 79 kb)

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Metherell, L., Chapple, J., Cooray, S. et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet 37, 166–170 (2005). https://doi.org/10.1038/ng1501

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