Functional characterization of naturally occurring mutations of the human adrenocorticotropin receptor: poor correlation of phenotype and gennotype

Several missense mutations of the ACTH receptor (MC2-R) gene have been asso ciated with the autosomal recessive syndrome of familial glucocorticoid def iciency. Attempts to demonstrate the functional role of these mutations hav e been confounded by difficulties in expression of the cloned receptor in c ells 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 f or this purpose. We demonstrate that several MC2-R mutations associated wit h familial glucocorticoid deficiency result in an impaired maximal cAMP res ponse (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 d efect in vitro and the age at clinical presentation and degree of clinical severity, as judged by basal and stimulated plasma cortisol concentration, is poor.