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The Majority of Adrenocorticotropin Receptor (Melanocortin 2 Receptor) Mutations Found in Familial Glucocorticoid Deficiency Type 1 Lead to Defective Trafficking of the Receptor to the Cell Surface

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom

Address all correspondence and requests for reprints to: Professor Adrian Clark, Centre for Endocrinology, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail: a.j.clark{at}qmul.ac.uk.

Context: There are at least 24 missense, nonconservative mutations found in the ACTH receptor [melanocortin 2 receptor (MC2R)] that have been associated with the autosomal recessive disease familial glucocorticoid deficiency (FGD) type 1. The characterization of these mutations has been hindered by difficulties in establishing a functional heterologous cell transfection system for MC2R. Recently, the melanocortin 2 receptor accessory protein (MRAP) was identified as essential for the trafficking of MC2R to the cell surface; therefore, a functional characterization of MC2R mutations is now possible.

Objective: Our objective was to elucidate the molecular mechanisms responsible for defective MC2R function in FGD.

Methods: Stable cell lines expressing human MRAP were established and transiently transfected with wild-type or mutant MC2R. Functional characterization of mutant MC2R was performed using a cell surface expression assay, a cAMP reporter assay, confocal microscopy, and coimmunoprecipitation of MRAP.

Results: Two thirds of all MC2R mutations had a significant reduction in cell surface trafficking, even though MRAP interacted with all mutants. Analysis of those mutant receptors that reached the cell surface indicated that four of six failed to signal, after stimulation with ACTH.

Conclusion: The majority of MC2R mutations found in FGD fail to function because they fail to traffic to the cell surface.