title: 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.
abstract: Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, usually without mineralocorticoid deficiency. Occasionally, the disorder is associated with alacrima and achalasia of the esophagus (triple A syndrome), suggesting potential heterogeneity in its etiology. Mutations in the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in 1 other family with IGD and 2 families with triple A syndrome. The proband with IGD was a homozygote for an A-->G substitution, changing tyrosine 254 to cysteine in the third extracellular loop of the receptor protein, probably interfering with ligand binding. Both of her parents were heterozygotes for this mutation, which was not detected in 100 normal alleles. No mutations were identified in the entire coding area of the ACTH receptor in the 2 families with triple A syndrome, supporting the idea of a developmental or postreceptor defect in this syndrome.
authors.affiliation: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tsigos
authors.forename: K
authors.initials: K
authors.lastname: Arai
authors.forename: A C
authors.initials: AC
authors.lastname: Latronico
authors.forename: A M
authors.initials: AM
authors.lastname: DiGeorge
authors.forename: R
authors.initials: R
authors.lastname: Rapaport
authors.forename: G P
authors.initials: GP
authors.lastname: Chrousos
mesh_terms: D000225:Adenine; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D003545:Cysteine; D004247:DNA / Q000097:blood; D017931:DNA Primers; D005260:Female; D005808:Genes, Recessive; D006580:Genetic Carrier Screening; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D005938:Glucocorticoids / Q000172:deficiency*; D006147:Guanine; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017433:Protein Structure, Secondary; D018043:Receptors, Corticotropin / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome; D014443:Tyrosine
chemical_list: D017931:DNA Primers; D005938:Glucocorticoids; D018043:Receptors, Corticotropin; D014443:Tyrosine; D006147:Guanine; D004247:DNA; D000225:Adenine; D003545:Cysteine