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Functional effects of genetic variants in the 11β‐hydroxylase (CYP11B1) gene
Author(s) -
Barr Marianne,
MacKenzie Scott M.,
Wilkinson Donna M.,
Holloway Christine D.,
Friel Elaine C.,
Miller Stephen,
MacDonald Tom,
Fraser Robert,
Connell John M. C.,
Davies Eleanor
Publication year - 2006
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2006.02673.x
Subject(s) - aldosterone synthase , steroid 11 beta hydroxylase , endocrinology , medicine , biology , missense mutation , aldosterone , corticosterone , gene , genetics , renin–angiotensin system , mutation , blood pressure , steroid , hormone
Summary Objective We previously described an association between the −344C/T 5′‐untranslated region (UTR) polymorphism in the CYP11B2 (aldosterone synthase) gene and hypertension with a raised aldosterone to renin ratio (ARR); the same genetic variant is also associated with impaired adrenal 11β‐hydroxylase efficiency. The −344 polymorphism does not seem to be functional, so is likely to be in linkage with variants in CYP11B1 that determine the associated variation in 11β‐hydroxylase efficiency. We therefore aimed to determine whether there is an association between CYP11B1 variants and hypertension and/or an altered ARR. Design and measurements We screened 160 subjects divided into four groups, normotensive controls, unselected hypertensive subjects, and hypertensive subjects with either a high (≥ 750) or low ARR (≤ 200), for variants in the coding region of CYP11B1 by single‐stranded conformation polymorphism (SSCP) and direct sequencing. The effects of these variants on enzyme function were assessed by conversion of 11‐deoxycortisol to cortisol and 11‐deoxycorticosterone (DOC) to corticosterone. Results Eight novel missense mutations were identified in the CYP11B1 gene that alter the encoded amino acids: R43Q, L83S, H125R, P135S, F139L, L158P, L186V and T196A. In each case they were heterozygous changes. However, no mutations were identified that could account for hypertension and/or a raised ARR. The variants L158P and L83S severely impaired enzyme function while R43Q, F139L, P135S and T196A enzymes resulted in product levels that were approximately 30–50% that of wild‐type levels. The variant enzymes H125R and L186V resulted in substrate‐specific alterations in enzyme function. H125R decreased conversion of 11‐deoxycortisol to cortisol and L186V increased 11‐deoxycortisol conversion. Neither had an effect on the conversion of DOC to corticosterone. Conclusion No variants were identified in the coding region of CYP11B1 that could account for hypertension and/or a raised ARR. However, this in vitro study identifies the importance of these affected residues to enzyme function and will inform subsequent studies of structure–function relationships.