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Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene.

Abstract
Two mutations in the same allele of the ACTH receptor (melanocortin 2 receptor, MC2R) associated with clinical hypersensitivity to ACTH have been described in a single case report. Using a stable Y6 cell expression system, we demonstrate that either the C21R or S247G mutations alone produce an inactive receptor with loss of ligand binding and responsiveness. However, the presence of both mutations in the same molecule leads to a receptor with a highly significant elevation in constitutive activity (basal cAMP accumulation for wild type expressing cells 199 +/- 11 pmol/mg protein; double mutant: 374 +/- 29 pmol/mg protein, P < 0.005. The co-expression of the normal MC2R allele results in the retention of a normal dose response to ACTH despite the presence of constitutive activity.
AuthorsFrancesca M Swords, Luke A Noon, Peter J King, Adrian J L Clark
JournalMolecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 213 Issue 2 Pg. 149-54 (Jan 15 2004) ISSN: 0303-7207 [Print] Ireland
PMID15062562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Ligands
  • Receptor, Melanocortin, Type 2
  • Adrenocorticotropic Hormone
  • Cyclic AMP
Topics
  • Adrenocorticotropic Hormone (metabolism)
  • Animals
  • Cell Line
  • Cyclic AMP (metabolism)
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation, Missense
  • Protein Binding
  • Radioligand Assay
  • Receptor, Melanocortin, Type 2 (chemistry, genetics, metabolism)
  • Transfection

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