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Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by progressive primary adrenal in- sufficiency, without mineralocorticoid deficiency. The cDNA and gene of the human ACTH receptor were recently cloned. The gene encodes a 297-amino acid protein that belongs to the G protein-coupled superfamily of membrane receptors. We hypothesized that the ACIH receptor gene might be defective in IGD. To examine this, we studied its genomic structure by PCR and direct sequencing in a 5-yr-old proband with the disease, his parents, and grandparents. The proband was a compound heterozygote for two different point mutations, one in each al- lele: (a) a substitution (C --T), also found in one allele of the mother and maternal grandmother, which introduced a prema- ture stop codon (TGA) at position 201 of the protein; this mu- tant receptor lacks its entire carboxy-terminal third and, if ex- pressed, should be unable to transduce the signal; and (b) a substitution (C -G), also found in one of the paternal alleles, which changed neutral serine " in the apolar third transmem- brane domain of the receptor to a positively charged arginine, probably disrupting the ligand-binding site. Standard ovine cor- ticotropin releasing hormone (oCRH) test in the heterozygote parents and maternal grandmother revealed exaggerated and prolonged ACTH responses, suggestive of subclinical resis- tance to ACTH. We conclude that IGD in this family appears to be due to defects of the ACTH receptor gene. The oCRH test appears to be useful in ascertaining heterozygosity in this syndrome. (J. Clin. Invest. 1993.92:2458-2461.) Key words: adre- nal insufficiency * ACTH receptor * CRH test * G protein-coupled receptors coma, which may result in death within the first 2 yr of life. Unless recognized and treated early, this condition may lead to chronic asthenia and failure to thrive. The disorder is occasionally associated with alacrima and achalasia of the esophagus, suggesting potential heterogeneity in its etiology (4, 5). Af- fected individuals have no cortisol or aldosterone responses to
Tsigos et al. (Mon,) studied this question.