Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene
- National Institutes of Health, Bethesda, MD (United States) Erasmus Univ. of Rotterdam (Netherlands)
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. The authors 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[prime]- and 3[prime]-flanking regions, the authors identified a 4-base deletion at the 3[prime]-boundary of exon 6 in one GR allele ([Delta][sub 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 (G[sub 1220]) in the proband, in one of her affected brothers and in her unaffected sister. This deletion in the glucocorticoid receptor gene was associated with the expression of only one allele and a decrease of GR protein by 50% in affected members of this glucocorticoid resistant family. The mutation identified in exon 2 did not segregate with the disease and appears to be of no functional significance. The presence of the null allele was apparently compensated for by increased cortisol production at the expense of concurrent hyperandrogenism. 40 refs., 3 figs.
- OSTI ID:
- 6589030
- Journal Information:
- Journal of Clinical Endocrinology and Metabolism; (United States), Vol. 76:3; ISSN 0021-972X
- Country of Publication:
- United States
- Language:
- English
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GLUCOCORTICOIDS
SENSITIVITY
RECEPTORS
GENE MUTATIONS
TRANSCRIPTION
MODULATION
ASPARAGINE
HYDROCORTISONE
SECRETION
SERINE
ADRENAL HORMONES
AMIDES
AMINO ACIDS
CARBOXYLIC ACIDS
CORTICOSTEROIDS
HORMONES
HYDROXY ACIDS
HYDROXY COMPOUNDS
KETONES
MEMBRANE PROTEINS
MUTATIONS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PREGNANES
PROTEINS
STEROID HORMONES
STEROIDS
550400* - Genetics