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Functional Characterization of Naturally Occurring Mutations of the Human Adrenocorticotropin Receptor: Poor Correlation of Phenotype and Genotype¹

Molecular Endocrinology Laboratory, Department of Chemical Endocrinology, St. Bartholomew’s and the Royal London School of Medicine and Dentistry (L.L.K.E., G.D.P., A.M., A.J.L.C.), West Smithfield, London, United Kingdom EC1A 7BE; and Children’s Hospital, Technical University Dresden (A.H.), D-01307 Dresden, Germany

Address all correspondence and requests for reprints to: Dr. Adrian J. L. Clark, Department of Chemical Endocrinology, St. Bartholomews Hospital, London EC1A 7BE, United Kingdom. E-mail a.j.clark{at}mds qmw.ac.uk

Several missense mutations of the ACTH receptor (MC2-R) gene have been associated with the autosomal recessive syndrome of familial glucocorticoid deficiency. Attempts to demonstrate the functional role of these mutations have been confounded by difficulties in expression of the cloned receptor in cells lacking endogenous melanocortin receptors. The Y6 cell line, a mutant derived from the Y1 cell line, lacks any endogenous MC2-R and can be used for this purpose. We demonstrate that several MC2-R mutations associated with familial glucocorticoid deficiency result in an impaired maximal cAMP response (S74I, I44M, R146H) or loss of sensitivity for cAMP generation (D103N, R128C, T159K) compared to the wild-type receptor. Considerable variation in clinical phenotype exists even for patients with identical mutations of the MC2-R, and correlation between the estimated severity of the receptor defect in vitro and the age at clinical presentation and degree of clinical severity, as judged by basal and stimulated plasma cortisol concentration, is poor.

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