We have located links that may give you full text access.
In silico and functional studies reveal novel loss-of-function variants of SRD5A2, but no variants explaining excess 5α-reductase activity.
Journal of Steroid Biochemistry and Molecular Biology 2019 January 29
Androgens are steroid hormones essential for human male and female development. Steroid reductases 5α (SRD5 As) are key enzymes in androgen biosynthesis. Mutations in the human SRD5 A2 are known to cause loss-of-function and severe 46,XY undervirilization. Gain-of-function variants have been suggested in androgen excess syndromes, but have not been found so far. Therefore we searched for gain-of-function mutations in the human SRD5 A2 gene which might explain hyperandrogenic disorders such as the polycystic ovary syndrome, premature adrenarche and prostate cancer. We screened databases for candidate variants and characterised them in silico with the help of a novel SRD5 A2 model. We selected 9 coding SNPs (A49 T, R50 A, P106 L, P106 A, N122 A, L167S, R168C, P173S, R227Q) that have not been described in manifesting individuals, and assessed their enzyme kinetic properties in HEK293 cells. SRD5 A2 activity was assessed by conversion of testosterone (T), progesterone (Prog) and androstenedione (Δ4 A) to their 5α-reduced metabolites. Variants R50 A and P173S showed partial activity with substrates T (34% and 28%) and Δ4 A (37% and 22%). With substrate Prog variants P106 L, P106 A, L167S and R168C in addition showed partial activity (15% to 64%). Functional testing of all other variants showed loss-of-function. As predicted in our in silico analysis, all coding SNPs affected enzyme activity, however none of them showed gain-of-function. Thus excess 5α-reductase activity might be rather regulated at the (post)-transcriptional and/or post-translational level. However through this work seven new coding SNPs were characterised which might be of clinical relevance. It is possible that individuals carrying these SNPs show a minor phenotype that is not yet identified.
Full text links
Related Resources
Trending Papers
Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.Clinical Research in Cardiology : Official Journal of the German Cardiac Society 2024 April 12
Proximal versus distal diuretics in congestive heart failure.Nephrology, Dialysis, Transplantation 2024 Februrary 30
Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.Mental Health Clinician 2023 October
World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.American Journal of Hematology 2024 March 30
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app