Clinical, Biochemical and Molecular Genetic Features of Glucocorticoid-Suppressible Hyperaldosteronism

Jamieson, Andrew (1995) Clinical, Biochemical and Molecular Genetic Features of Glucocorticoid-Suppressible Hyperaldosteronism. PhD thesis, University of Glasgow.

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Abstract

Human hypertension is a multifactorial disorder affecting up to 20% of the population of developed countries. The hypertensive phenotype varies between individuals and both environmental and genetic factors may be important in determining an individuals blood pressure. Although the majority of cases of hypertension are labelled as primary (or essential) implying that the aetiology of the hypertension is unknown, a genetically inherited form of hypertension, glucocorticoid-suppressible hyperaldosteronism (GSH), has been characterised and studied in detail in this thesis. GSH is an inherited form of hypertension characterised by elevated plasma aldosterone concentrations with suppression of plasma renin activity, hypertension, hypokalaemia, and an autosomal dominant mode of inheritance. A chimeric 11beta-hydroxylase/aldosterone synthase gene has been described in patients with GSH. This gene, presumably a result of unequal crossing-over at meiosis, has ACTH- inducible aldosterone synthase activity demonstrable in vivo which explains the observed clinical and biochemical phenotype of GSH. A technique for detection of individuals with GSH was devised based on the detection of the chimeric gene by probing of a Southern blot of BamHI digested genomic DNA. Normal individuals possess two hybridising species, a 8.4 kb band (11beta-hydroxylase, CYP11B1) and a 4.4 kb band (aldosterone synthase, CYP11B2) when probed with a 32P-labelled CYP11B1 exon 2-5 probe. Affected individuals possess the two normal bands and a third 6.3 kb band corresponding to the chimeric gene. This method was used to screen five kindreds affected by GSH and to detect 19 affected individuals. Treatment of affected individuals with the oral glucocorticoid dexamethasone 0.5 mg q.d.s. resulted in a fall in blood pressure and plasma aldosterone concentrations, and a normalisation of plasma renin concentration and statistically significant rise in plasma potassium concentration. Further evaluation of kindreds with GSH revealed a wide variation in the clinical phenotype of GSH, particularly in terms of blood pressure. A novel observation on the role of parental origin of the disease gene was made. Patients inheriting the chimeric gene from their mother had higher blood pressures and higher plasma aldosterone concentrations than those inheriting the condition from their father. The exact nucleotide sequence of the chimeric genes in the 5 kindreds was determined by the dideoxy-chain termination method. Three kindreds possessed chimeric genes indistinguishable by sequencing, whilst the other two kindreds had unique crossovers. All crossover events occurred within the exon 3-intron 4 region of the chimeric genes, in keeping with previously published observations. The structure of the chimeric gene, i.e. the position of the crossover site, has no effect on the clinical phenotype. In addition to determining the site of the crossover region in the kindreds, a diallelic polymorphism in the promoter region of the aldosterone synthase gene was identified. The C/T single nucleotide polymorphism lies within the Steroidogencic Factor-1 binding region of the promoter at position -340. One allele of this polymorphism was shown to be in linkage disequilibrium with GSH suggesting a degree of allelic bias in the origin of the chimeric genes causing GSH. Individuals with GSH show impaired basal and ACTH-stimulated 11beta-hydroxylation ability compared with normal controls. Basal molar plasma ratios of DOC:B and S:F are raised in patients with GSH, but ACTH-stimulation results in differential effects on the 17-hydroxy- and 17-deoxy- pathways. In the 17-hydroxy- pathway (cortisol synthesis) the impaired 11beta-hydroxylation is exacerbated by ACTH, whereas in the 17-deoxy- pathway (aldosterone synthesis) ACTH stimulation acts to rectify the abnormality. Basal molar plasma B:ALDO ratio (an index of aldosterone synthase activity) was lower in patients with GSH than controls. ACTH stimulation resulted in a rise in B:ALDO ratio in patients with GSH and a fall in normal controls. The reasons for the observed differences are unclear but may arise as a result of pseudosubstrate inhibition of 11beta-hydroxylation by compounds such as 18-hydroxycortisol, or as a result of altered gene expression in the adrenal cortex in GSH. Finally, a study of the effect of lifelong hyperaldosteronism on echocardiographically determined left ventricular mass index was performed. The study revealed that GSH did not predispose to premature or excessive left ventricular hypertrophy despite evidence that aldosterone can produce myocardial fibrosis. However, a significant positive correlation between left ventricular mass and plasma aldosterone concentration in patients with GSH was noted. The study of GSH provides a framework for assessing the possible factors involved in the development of human essential hypertension. The observations contained in this thesis shed light on how a single gene disorder may cause hypertension and how other factors such as intrauterine influences may modulate the genetic component of hypertension. Further studies of GSH may reveal the mechanisms underlying altered corticosteroidogenesis in essential hypertension.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: John Connell
Keywords: Biochemistry, Genetics
Date of Award: 1995
Depositing User: Enlighten Team
Unique ID: glathesis:1995-74819
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 13 Nov 2019 15:58
Last Modified: 13 Nov 2019 15:58
URI: http://theses.gla.ac.uk/id/eprint/74819

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