Variation at the Glucocorticoid Receptor Gene Locus: Physiological and Pathophysiological Consequences

Blackhurst, Guthrie (2000) Variation at the Glucocorticoid Receptor Gene Locus: Physiological and Pathophysiological Consequences. PhD thesis, University of Glasgow.

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Glucocorticoids are important hormones in the regulation of carbohydrate, lipid and protein metabolism, and cardiovascular and central nervous function. The result of the syndrome of glucocorticoid excess is hyperglycaemia, insulin resistance, hyperlipidaemia, central obesity, hypertension, and the accelerated development of atheroma. In rare genetic conditions resulting in glucocorticoid resistance, excess ACTH drive to the adrenal results in excess mineralocorticoid and androgen production and increased cardiovascular morbidity. Recently, an RFLP of the glucocorticoid receptor situated within the promoter or intronic non-coding parts of the gene was found in excess in patients with obesity, insulin resistance, hypertension and hyperlipidaemia. It remains unknown however, whether these findings are due to altered glucocorticoid secretion, altered peripheral glucocorticoid sensitivity, or to linkage disequilibrium with a nearby gene. The purpose of this project was to examine glucocorticoid receptor gene structure and receptor function in a large cohort of normal subjects with carefully characterised cardiovascular and metabolic variables to assess any association between glucocorticoid receptor function and cardiovascular and metabolic risk factors. The glucocorticoid receptor gene was screened for common polymorphisms in a panel of 80 normal subjects by the techniques of PCR-SSCP with subsequent sequencing of amplicons suspected of containing mutations. This strategy revealed a complex mutation with 15 nucleotide substitutions in exon 5 in 4 subjects. The mutation resulted in a threonine to alanine substitution in the coded protein. Receptor binding assays were conducted on 2 large cohorts of subjects from the Scottish Twin Study and the Midspan Study. Both studies demonstrated a previously unreported seasonal component to glucocorticoid binding with lower Kd for dexamethasone binding in summer months than winter. These studies were extended to serial observations of receptor binding in 9 normal male subjects that confirmed the same seasonal effect on receptor Kd. Furthermore, there was a significant interaction with daylight and environmental temperature in all populations. Further in vitro work showed co-incubation of lymphocytes with physiological levels of melatonin resulted in a higher Kd value for dexamethasone binding, which would be consistent with the climatic observations noted. We conclude that the glucocorticoid receptor gene carries very few mutations in normal subjects, and the effect of an uncommon mutation in exon 5 will require further work to assess its contribution to cardiovascular risk. Glucocorticoid receptor binding is, however, modulated by melatonin presumably through the effect of daylight and this observation may have implications for the wide range of physiological processes controlled by this endocrine system.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: John Connell
Keywords: Genetics
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-76148
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 16:34
Last Modified: 19 Nov 2019 16:34

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