Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene
Abstract
The clinical syndrome of generalized, compensated glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hyper- or hypocortisolism, and manifestations of androgen and/or mineralocorticoid excess. This condition results from partial failure of the glucocorticoid receptor (GR) to modulate transcription of its target genes. We studied the molecular mechanisms of this syndrome in a Dutch kindred, whose affected members had hypercortisolism and approximately half of normal GRs, and whose proband was a young woman with manifestations of hyperandrogenism. Using the polymerase chain reaction to amplify and sequence each of the nine exons of the GR gene alpha, along with their 5'- and 3'-flanking regions, we identified a 4-base deletion at the 3'-boundary of exon 6 in one GR allele (delta 4), which removed a donor splice site in all three affected members studied. In contrast, the sequence of exon 6 in the two unaffected siblings was normal. A single nucleotide substitution causing an amino acid substitution in the amino terminal domain of the GR (asparagine to serine, codon 363) was also discovered in exon 2 of the other allele (G1220) in the proband, in one of her affected brothers and in her unaffected sister. The functional importance of this mutation was tested in a cotransfection study using the recombinant expression vector pRShGR-Ser363 and the glucocorticoid responsive vector mouse mammary tumor virus-chloramphenicol transferas…
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Patients with familial glucocorticoid resistance may be homozygous for missense mutations or heterozygous for a gene deletion, so that in each case some GR activity remains.
“Patients may be homozygous for missense mutations (635) or heterozygous for a gene deletion (636), so that in each case some GR activity remains.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [636]
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- Authors
- Karl, M., Lamberts, S. W., Detera-Wadleigh, S. D., Encio, I. J., Stratakis, C. A., Hurley, D. M., Accili, D., & Chrousos, G. P.
- Affiliations
- National Institutes of Health (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1993-03
- Volume
- 76
- Issue
- 3
- Pages
- 683-689
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1968680063
- Cited by
- 241
- References
- 1
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 7 · 2017: 2 · 2016: 5 · 2015: 8 · 2014: 7 · 2013: 6 · 2012: 8
- FWCI
- 10.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- glucocorticoid receptor gene, exon 6 deletion, hypercortisolism, hyperandrogenism, null alleles, amino acid substitutions, N-terminal domain
- MeSH terms
- Adult, Amino Acid Sequence, DNA, Recombinant, Drug Resistance, Female, Glucocorticoids, Humans, Male, Molecular Sequence Data, Mutation, Nucleic Acid Hybridization, Pedigree, Receptors, Glucocorticoid, Polymerase Chain Reaction, Gene Deletion
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