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GSH was first reported in 1966 and is an autosomal dominant form of low-renin hypertension characterised by aldosterone excess under the control of ACTH rather the normal principal secretogogue, angiotensin II. There are two important consequences of this; firstly, that there is dysregulation of aldosterone secretion because of loss of negative feedback loop (aldosterone does not suppress ACTH secretion). Secondly, the exogenous administration of a glucocorticoid such as dexamethasone, by decreasing ACTH secretion results in suppression of aldosterone secretion and can be used therapeutically. Long-term glucocorticoid therapy leads to reactivation and normal regulation of the renin-angiotensin-aldosterone axis. A further characteristic of GSH is the secretion of large quantities of 18-OH and 18-oxo corticosterone / cortisol metabolites, again under the control of ACTH, and while there is some overlap with levels seen in APA, these provide a diagnostic marker for the condition.
The molecular basis for GSH was described by Lifton and colleagues following the cloning and characterisation of the two final enzymes in cortisol and aldosterone synthesis, 1-beta-hydroxylase and aldosterone synthase respectively. 11-beta-hydroxylase converts 11-deoxycortisol to cortisol in the zona fasciculata and aldosterone synthase corticosterone to aldosterone through an enzymatic step involving 11-beta-hydroxylation and 18-hydroxylation and oxidation. These enzymes are encoded by two genes, CYP11B1 and CYP11B2 lying in tandem on chromosome 8. Despite the similarity in the coding sequences of 11$-hydroxylase and aldosterone synthase (>95%), their 5’ sequences differ permitting regulation of 11-beta-hydroxylase by ACTH through cAMP and aldosterone synthase by AII through intracellular Ca2+, thereby establishing functional zonation of the adrenal cortex. In GSH a hybrid gene is formed at meiosis from unequal cross over of the CYP11B1 and CYP11B2 genes and this contains proximal components of CYP11B1 and distal components of CYP11B2. So long as the breakpoint of the hybrid gene is in or 5’ to exon IV of the CYP11B1 gene, the product of this gene can synthesise aldosterone, but is now under the control of ACTH. The chimaeric gene can be detected by Southern blotting or by long PCR providing a screening test for GSH and the facility for pre-natal diagnosis.
Following such advances, numerous kindreds have been reported with GSH. Studies on larger cohorts indicate that potassium may be normal in up to 50% of cases and there exists a poor correlation between genotype and phenotype (potassium, BP) both between and within families. Severe mineralocorticoid excess has been reported in some affected cases of GSH, but in other members of the same family, the gene defect has caused no abnormal phenotype. Patients with GSH are more susceptible to cerebrovascular haemorrhage.
by P.M. Stewart: Adrenal Cortex - Renin-Angiotensin-Aldosterone Axis and Hypertension
Dr. Gabriele Dekomien
Humangenetik
Gebäude MA 5
Ruhr-Universität
Universitätsstr. 150
44801 Bochum
GermanyTel.: +49 234 32 25764
Fax: +49 234 32 14196
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