A NOVEL MUTATION OF THE ADRENOCORTICOTROPIN RECEPTOR (ACTH-R) GENE INA FAMILY WITH THE SYNDROME OF ISOLATED GLUCOCORTICOID DEFICIENCY, BUTNO ACTH-R ABNORMALITIES IN 2 FAMILIES WITH THE TRIPLE-A SYNDROME

Isolated glucocorticoid deficiency (IGD) is an autosomal recessive dis order characterized by primary adrenocortical insufficiency, usually w ithout mineralocorticoid deficiency. Occasionally, the disorder is ass ociated with alacrima and achalasia of the esophagus (triple A syndrom e), suggesting potential heterogeneity in its etiology, Mutations in t he ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH r eceptor gene in 1 other family with IGD and 2 families with triple A s yndrome. The proband with IGD was a homozygote for an A-->G substituti on, changing tyrosine 254 to cysteine in the third extracellular loop of the receptor protein, probably interfering with ligand binding. Bot h of her parents were heterozygotes for this mutation, which was not d etected in 100 normal alleles. No mutations were identified in the ent ire coding area of the ACTH receptor in the 2 families with triple A s yndrome, supporting the idea of a developmental or postreceptor defect in this syndrome.