Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency

Abstract

The hereditary syndrome of unresponsiveness to ACTH is a rare autosomal recessive disorder characterized by low levels of serum cortisol and high levels of plasma ACTH. There is no cortisol response to exogenous ACTH. Recent cloning of the human ACTH receptor gene has enabled us to study this gene in patients with glucocorticoid deficiency. By using the PCR to amplify the coding sequence of the ACTH receptor gene, we identified three mutations in two unrelated patients. One mutation present in homozygous form converted the negatively charged Asp107, located in the third transmembrane domain, to an uncharged Asn residue. The second patient was a compound heterozygote: the paternal allele contained a one-nucleotide insertion leading to a stop codon within the third extracellular loop, and the maternal allele contained a point mutation converting Cys251 to Phe, also in the third extracellular loop. Normal and mutant ACTH receptor genes were expressed in the M3 cell line, and intracellular cAMP production in response to ACTH was measured. For the mutant receptors, no response to physiological ACTH concentrations was detected, suggesting an impaired binding of ACTH to the receptors and/or an altered coupling to the adenylate cyclase effector.

Familial Glucocorticoid Deficiency with a Point Mutation in the ACTH Receptor: A Case Report

“…In newborns, symptoms of hypoglycemia can be subtle, so a high index of suspicion is needed (3). Often these patients are significantly jaundiced and may require phototherapy (7). In some cases this appears to result from a transient hepatitis (8).…”

“…All five of these receptors can bind ACTH to some extent, but MC2R binds ACTH at the highest affinity, is expressed almost exclusively in the adrenal cortex, and hence is the physiological ACTH receptor (3). After the MC2R gene was cloned (10), approximately 20 different MC2R mutations have been reported in patients with FGD (6, 7, 10). MC2R is a 297-amino acid protein, encoded by a gene on chromosome 18p11.2 (5).…”

“…This missense mutation is in the first extracellular loop of the receptor and may impair ACTH binding (4, 6, 11). However, the etiology of FGD is heterogeneous, and not all patients with FGD have been found to have MC2R gene mutations (4, 7). Patients with FGD who have mutations in the MC2R gene are said to have FGD type 1, and patients in whom no such mutations are found have FGD type 2 (4).…”

Familial Glucocorticoid Deficiency Type 1 due to a Novel Compound Heterozygous <i>MC2R</i> Mutation

“…The adjacent naturally occurring mutation p.Ile44Met results in a near loss of signal transduction but shows virtually normal binding parameters [11]. On the other hand, the p.Val45Ile mutation, found as a heterozygous mutation in one FGD patient with a normal second allele, did not significantly alter the signal transduction pathway and was assumed to be a polymorphism [12]. This can be confirmed by molecular modeling in that the alpha-helix of TMD I is not changed with the Val45Ile polymorphism.…”

Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

“…In comparison, homozygous nonsense mutations are rare. The functional consequence of various MC2R mutations has been demonstrated by a number of groups [36,40,41,42,43,44]. To date there is no strong evidence to suggest that heterozygous carriers, i.e.…”