Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene

Tsigos, C; Arai, K; Hung, W; Chrousos, G P

doi:10.1172/jci116853

Cited by 183Adrenal Hormones and DisordersStress Responses and CortisolMetabolism and Genetic Disorders

Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene

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Tsigos, C, Arai, K, Hung, W, Chrousos, G P·1993·Journal of Clinical Investigation

DOI 10.1172/jci116853PMC PMC288430

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Abstract

Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by progressive primary adrenal insufficiency, 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 ACTH 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 allele: (a) a substitution (C-->T), also found in one allele of the mother and maternal grandmother, which introduced a premature stop codon (TGA) at position 201 of the protein; this mutant receptor lacks its entire carboxy-terminal third and, if expressed, should be unable to transduce the signal; and (b) a substitution (C-->G), also found in one of the paternal alleles, which changed neutral serine120 in the apolar third transmembrane domain of the receptor to a positively charged arginine, probably disrupting the ligand-binding site. Standard ovine corticotropin releasing hormone (oCRH) test in the heterozygote parents and maternal grandmother revealed exaggerated and prolonged ACTH responses, suggestive of subclinical resistance 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.

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Patients with inactivating mutations in the ACTH receptor (MC2R) or the LH/hCG receptor make negligible steroids from the affected glands.
“Patients with inactivating mutations in the ACTH receptor (MC2R) (159) or the LH/hCG receptor (160) make negligible steroids from the affected glands.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [159]
The Methods report that the patient with ACTH-receptor mutations had serum cortisol below 1 μg/dl and no cortisol increase after ACTH injection. But aldosterone was normal, so the paper supports negligible glucocorticoid production, not negligible production of steroids generally. The LH/hCG-receptor clause is attached to a different citation and is not assessed here. (LLM, conf=0.88)
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Authors: Tsigos, C., Arai, K., Hung, W., & Chrousos, G. P.
Affiliations: National Institutes of Health (US)
ORCID: Arai, K
Chrousos, G P
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1993-11-01
Volume: 92
Issue: 5
Pages: 2458-2461
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci116853
PMC: PMC288430
OpenAlex: W2055723678
Semantic Scholar: ba08231d871519ab7bf0f7184b630e96181458b1
Cited by: 182
References: 21
Citations by year: 2026: 1 · 2024: 2 · 2023: 1 · 2022: 6 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 3 · 2012: 3
FWCI: 7.21
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords: Addison's disease, compound heterozygosity, G protein-coupled receptors, premature stop codon, ACTH resistance, autosomal recessive inheritance
MeSH terms: Adrenocorticotropic Hormone, Adult, Amino Acid Sequence, Base Sequence, Child, Preschool, Female, Genes, Recessive, Glucocorticoids, Heterozygote, Homozygote, Humans, Hydrocortisone, Lipid Metabolism, Inborn Errors, Male, Molecular Sequence Data, Pedigree, Genome, Human, Point Mutation, Sequence Analysis, DNA, Receptors, Corticotropin

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Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene

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