{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:55:28Z","timestamp":1767192928336,"version":"3.38.0"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p><jats:italic>SRD5A2<\/jats:italic> gene variants are associated with deficiency of steroid 5\u03b1-reductase type 2, which is an autosomal recessive disorder of sex development (DSD) present in 46,XY males with ambiguous genitalia. To determine the causality of the disorder, this study involved genetic screening of <jats:italic>SRD5A2<\/jats:italic> in six unrelated patients with this condition. Polymerase chain reaction (PCR) assays excluded large duplications, insertions, or deletions, while bidirectional Sanger sequencing identified 15 single-nucleotide variants (SNVs), six patients with 46,XY-DSD carrying pathogenic non-synonymous SNVs (nsSNVs), and three subjects who were DSD-free with novel synonymous SNVs (sSNVs). Genomic outcomes showed that 9 non-synonymous coding SNVs are linked to patients with <jats:italic>SRD5A2<\/jats:italic>-associated steroid 5\u03b1-reductase type 2 deficiency (c.169G\u2009&gt;\u2009C: p.E57Q; c.145G\u2009&gt;\u2009A: p.A49T\/c.686T\u2009&gt;\u2009C: p.F229S; c.100G\u2009&gt;\u2009A: p.G34R\/c.344G\u2009&gt;\u2009A: p.G115D; c.591G\u2009&gt;\u2009T: p.E197D; c.92C\u2009&gt;\u2009T: p.S31F\/c.481A\u2009&gt;\u2009C: p.I161L (a novel missense variant; <jats:italic>K<\/jats:italic><jats:sub><jats:italic>m<\/jats:italic><\/jats:sub>,<jats:sub><jats:italic>app<\/jats:italic><\/jats:sub> =\u2009 1.19 \u00b1\u2009 0.1 \u03bcM, <jats:italic>V<\/jats:italic><jats:sub><jats:italic>max<\/jats:italic><\/jats:sub>,<jats:sub><jats:italic>app<\/jats:italic><\/jats:sub> =\u2009 688 \u00b1\u2009 145.8 pmol\/mg P\/min); c.686T\u2009&gt;\u2009C: p.F229S). This analysis also highlighted 2 non-disease-causing sSNVs in three DSD-free subjects (c.243G\u2009&gt;\u2009T: p.T81\u2009=\u2009; c.594C\u2009&gt;\u2009T: p.I198=). These silent mutations or sSNVs in the <jats:italic>SRD5A2<\/jats:italic> gene have no functional consequences and might not be involved in steroid 5\u03b1-reductase 2 de\ufb01ciency. The identification of these sSNVs in both healthy controls and patients might suggest natural genetic variability with a very low allele frequency in the Mexican population. Furthermore, these findings indicated that nsSNVs in the <jats:italic>SRD5A2<\/jats:italic> gene altered normal development of external male genitalia, supporting their pathogenicity.<\/jats:p>","DOI":"10.1371\/journal.pone.0316497","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T18:34:30Z","timestamp":1741199670000},"page":"e0316497","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel non-synonymous and synonymous gene variants of SRD5A2 in patients with 46,XY-DSD and DSD-free subjects"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1014-3262","authenticated-orcid":true,"given":"Luis","family":"Ramos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,3,5]]},"reference":[{"issue":"9","key":"pone.0316497.ref001","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.1016\/S0021-9258(19)41542-1","article-title":"Dihydrotestosterone formation in cultured human fibroblasts. Comparison of cells from normal subjects and patients with familial incomplete male pseudohermaphroditism, Type 2","volume":"250","author":"JD Wilson","year":"1975","journal-title":"J Biol Chem"},{"issue":"18","key":"pone.0316497.ref002","doi-asserted-by":"crossref","first-page":"7168","DOI":"10.1016\/S0021-9258(19)40924-1","article-title":"Diminished 5alpha-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male pseudohermaphroditism, type 2","volume":"250","author":"RJ Moore","year":"1975","journal-title":"J Biol Chem"},{"issue":"19","key":"pone.0316497.ref003","doi-asserted-by":"crossref","first-page":"5895","DOI":"10.1016\/S0021-9258(17)33036-3","article-title":"Steroid 5alpha-reductase in cultured human fibroblasts. 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