Effects of genetic variation in the aldosterone synthase (CYP11B2) gene on enzyme function

Holloway, C.D. et al. (2009) Effects of genetic variation in the aldosterone synthase (CYP11B2) gene on enzyme function. Clinical Endocrinology, 70(3), pp. 363-371. (doi:10.1111/j.1365-2265.2008.03383.x)

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Publisher's URL: http://dx.doi.org/10.1111/j.1365-2265.2008.03383.x

Abstract

<b>Objective</b>  Evidence suggests that high levels of aldosterone lead to hypertension and increased risk of cardiovascular disease. Around 15% of patients with essential hypertension have a raised aldosterone to renin ratio (ARR) suggesting that aldosterone production is inappropriately high in relation to its principal agonist angiotensin II. This may be due to increased activity of aldosterone synthase caused by genetic variation in the CYP11B2 gene. We screened the coding region of human CYP11B2 for genetic variants and tested their effects on function in vitro.<p></p> <b>Protocol</b>  Normotensive subjects (n = 69) were screened for sequence variants in the coding region of CYP11B2 by single-stranded conformation polymorphism (SSCP) analysis and sequencing. The effects of nonsynonymous variants on enzyme activity were assessed in JEG-3 cells transiently transfected with wild-type or variant expression plasmids. The conversion of the substrate 11-deoxycorticosterone (DOC) to corticosterone (B) and aldosterone was measured.<p></p> <b>Results</b>  Twenty variants were detected in CYP11B2 and eight analysed functionally (Arg87Gly, Asn281Thr, Gly288Ser, Lys296Asn, Asp335Asn, Gln404Arg, Ala414Pro and His439Tyr). Corticosterone synthesis was unaltered and aldosterone synthesis reduced in variant Arg87Gly; Asn281Thr increased corticosterone and decreased aldosterone production; Gly288Ser increased corticosterone production and abolished aldosterone production; Lys296Asn reduced both corticosterone and aldosterone production; Asp335Asn increased corticosterone synthesis but did not affect aldosterone production. Variants Gln404Arg, Ala414Pro and His439Tyr showed increases in both corticosterone and aldosterone synthesis compared to the wild-type.<p></p> <b>Conclusion</b>  The study confirms the genetic variability of the CYP11B2 gene and provides us with additional valuable structure–function information.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Barr, Mrs Moira and Miller, Dr Steven and Miller, Dr Susan and Friel, Mrs Elaine and Davies, Professor Eleanor and Miller, Mr Stephen and Wilson-Davies, Dr Eleri and Connell, Professor John and MacKenzie, Dr Scott and Fraser, Prof Robert and MacKenzie, Dr Sandra
Authors: Holloway, C.D., MacKenzie, S., MacKenzie, S.M., Fraser, R., Miller, S.C., Miller, S.K., Miller, S., Barr, M., Wilkinson, D., Forbes, G.H., Friel, E.C., Connell, J., Davies, E., and Davies, E.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Clinical Endocrinology
Publisher:Wiley for the Society for Endocrinology
ISSN:0300-0664
ISSN (Online):1365-2265
Published Online:15 August 2008
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences