Functional effects of genetic variants in the 11β-hydroxylase (CYP11B1) gene

TY - JOUR

T1 - Functional effects of genetic variants in the 11β-hydroxylase (CYP11B1) gene

AU - Barr, Marianne

AU - MacKenzie, Scott M.

AU - Wilkinson, Donna M.

AU - Holloway, Christine D.

AU - Friel, Elaine C.

AU - Miller, Stephen

AU - MacDonald, Tom

AU - Fraser, Robert

AU - Connell, John M.C.

AU - Davies, Eleanor

PY - 2006/12

Y1 - 2006/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/33751087743

U2 - 10.1111/j.1365-2265.2006.02673.x

DO - 10.1111/j.1365-2265.2006.02673.x

M3 - Article

C2 - 17121536

AN - SCOPUS:33751087743

SN - 0300-0664

VL - 65

SP - 816

EP - 825

JO - Clinical Endocrinology

JF - Clinical Endocrinology

IS - 6

ER -