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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.

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          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.

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          Author and article information

          Journal
          Mol. Cell. Endocrinol.
          Molecular and cellular endocrinology
          Elsevier BV
          0303-7207
          0303-7207
          Jan 15 2004
          : 213
          : 2
          Affiliations
          [1 ] Department of Endocrinology, Barts and the London, Queen Mary University of London, London EC1A 7BE, UK.
          Article
          S0303720703003940
          10.1016/j.mce.2003.10.052
          15062562
          0499db6a-d060-4dc5-8d5e-592094cac3c1
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