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

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.

[1]  A. Clark,et al.  Adrenocorticotropin insensitivity syndromes. , 1998, Endocrine reviews.

[2]  C. Stratakis,et al.  Genetic heterogeneity of adrenocorticotropin (ACTH) resistance syndromes: identification of a novel mutation of the ACTH receptor gene in hereditary glucocorticoid deficiency. , 1998, Molecular genetics and metabolism.

[3]  S. Sugano,et al.  Human ACTH hypersensitivity syndrome associated with abnormalities of the ACTH receptor gene , 1998, Clinical endocrinology.

[4]  K. Catt,et al.  Mutations of the conserved DRS motif in the second intracellular loop of the gonadotropin-releasing hormone receptor affect expression, activation, and internalization. , 1997, Molecular endocrinology.

[5]  D. Faury,et al.  Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency. , 1996, The Journal of clinical endocrinology and metabolism.

[6]  C. Tsigos,et al.  A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome. , 1995, The Journal of clinical endocrinology and metabolism.

[7]  R. Qiu,et al.  Adrenocorticotropin‐resistant mutants of the Y1 adrenal cell line fail to express the adrenocorticotropin receptor , 1995, Journal of cellular physiology.

[8]  S. Asa,et al.  Are activating mutations of the adrenocorticotropin receptor involved in adrenal cortical neoplasia? , 1995, Life sciences.

[9]  C. Tsigos,et al.  No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms. , 1995, The Journal of clinical endocrinology and metabolism.

[10]  G Vriend,et al.  A common step for signal transduction in G protein-coupled receptors. , 1994, Trends in pharmacological sciences.

[11]  P. Sokoloff,et al.  Molecular cloning and characterization of the rat fifth melanocortin receptor. , 1994, Biochemical and biophysical research communications.

[12]  M. Parmentier,et al.  Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. , 1994, Biochemistry.

[13]  E. El-Fakahany,et al.  An arginine residue conserved in most G protein-coupled receptors is essential for the function of the m1 muscarinic receptor. , 1994, Molecular pharmacology.

[14]  Israel Hanukoglu,et al.  cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor. , 1994, Biochimica et biophysica acta.

[15]  A. Clark,et al.  Functional characterization of the cloned human ACTH receptor: impaired responsiveness of a mutant receptor in familial glucocorticoid deficiency. , 1993, Biochemical and biophysical research communications.

[16]  C. Tsigos,et al.  Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene. , 1993, The Journal of clinical investigation.

[17]  M. Birnbaumer,et al.  Nephrogenic diabetes insipidus. A V2 vasopressin receptor unable to stimulate adenylyl cyclase. , 1993, The Journal of biological chemistry.

[18]  J. Baldwin The probable arrangement of the helices in G protein‐coupled receptors. , 1993, The EMBO journal.

[19]  A. Clark,et al.  Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor , 1993, The Lancet.

[20]  S. Chaki,et al.  Domains for G-protein coupling in angiotensin II receptor type I: studies by site-directed mutagenesis. , 1992, Biochemical and biophysical research communications.

[21]  M. Mortrud,et al.  The cloning of a family of genes that encode the melanocortin receptors. , 1992, Science.

[22]  C. Fraser,et al.  In vitro mutagenesis and the search for structure-function relationships among G protein-coupled receptors. , 1992, The Biochemical journal.

[23]  K. Catt,et al.  The mas oncogene enhances angiotensin-induced [Ca2+]i responses in cells with pre-existing angiotensin II receptors. , 1991, Biochimica et biophysica acta.

[24]  A. Penhoat,et al.  Corticotropin positively regulates its own receptors and cAMP response in cultured bovine adrenal cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[25]  L. Stuve,et al.  Characterization of corticotropin receptors in human adrenocortical cells. , 1986, The Journal of clinical endocrinology and metabolism.

[26]  E. Escher,et al.  Adrenocorticotropin receptors in rat adrenal glomerulosa cells. , 1985, Endocrinology.

[27]  J. Ramachandran,et al.  Characterization of corticotropin receptors on adrenocortical cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Maguire,et al.  Relationship between the beta-adrenergic receptor and adenylate cyclase. , 1977, The Journal of biological chemistry.

[29]  R. A. Harkness,et al.  Familial glucocorticoid deficiency. Studies of diagnosis and pathogenesis. , 1975, Archives of disease in childhood.

[30]  B. Brown,et al.  A simple and sensitive saturation assay method for the measurement of adenosine 3':5'-cyclic monophosphate. , 1971, The Biochemical journal.

[31]  J. Toppari,et al.  Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families. , 1995, The Journal of clinical endocrinology and metabolism.