{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:56:45Z","timestamp":1790024205164,"version":"4.0.1"},"reference-count":57,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T00:00:00Z","timestamp":1674000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 ES013508"],"award-info":[{"award-number":["P30 ES013508"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-ES0199851"],"award-info":[{"award-number":["T32-ES0199851"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-GM133398"],"award-info":[{"award-number":["T32-GM133398"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in SRD5A2, HSD17B3, and HSD3B2 genes that lead to disordered sexual development, salt wasting, and other severe disorders provide a glimpse of the impacts of mutations in steroid hormone transforming enzymes. In a departure from these established examples, this review examines disease-associated germline coding mutations in steroid-transforming members of the human aldo-keto reductase (AKR) superfamily. We consider two main categories of missense mutations: those resulting from nonsynonymous single nucleotide polymorphisms (nsSNPs) and cases resulting from familial inherited base pair substitutions. We found mutations in human AKR1C genes that disrupt androgen metabolism, which can affect male sexual development and exacerbate prostate cancer and polycystic ovary syndrome (PCOS). Others may be disease causal in the AKR1D1 gene that is responsible for bile acid deficiency. However, given the extensive roles of AKRs in steroid metabolism, we predict that with expanding publicly available data and analysis tools, there is still much to be uncovered regarding germline AKR mutations in disease.<\/jats:p>","DOI":"10.3390\/ijms24031873","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T03:04:44Z","timestamp":1674011084000},"page":"1873","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Germline Mutations in Steroid Metabolizing Enzymes: A Focus on Steroid Transforming Aldo-Keto Reductases"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5101-2245","authenticated-orcid":false,"given":"Andrea J.","family":"Detlefsen","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5735-9896","authenticated-orcid":false,"given":"Ryan D.","family":"Paulukinas","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3937-1066","authenticated-orcid":false,"given":"Trevor M.","family":"Penning","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1743-7075-7-47","article-title":"Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones","volume":"7","author":"Hu","year":"2010","journal-title":"Nutr. 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