{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T04:48:03Z","timestamp":1777265283364,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pathogenic\n                      <jats:italic>POR<\/jats:italic>\n                      variants cause P450 oxidoreductase deficiency, a rare steroidogenesis disorder. Missense changes are well characterized, but the clinical and molecular consequences of splicing defects remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We identified a novel homozygous splice variant (c.1249-2A&amp;gt;C) in a patient with disorders of sex development and Antley-Bixler syndrome -like skeletal malformations. By reviewing 12 published cases and performing minigene assays on five variants (c.731\u00a0+\u00a01G&amp;gt;A, c.732-2A&amp;gt;T, c.947\u00a0+\u00a01G&amp;gt;A, c.948-30G&amp;gt;A, c.1249-2A&amp;gt;C), we characterized their splicing outcomes. Structural consequences were predicted using AlphaFold; nonsense-mediated mRNA degradation was assessed for c.1249-2A&amp;gt;C using cycloheximide block.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>c.731\u00a0+\u00a01G&amp;gt;A and c.947\u00a0+\u00a01G&amp;gt;A caused intron retention with premature termination, deleting FAD\/NADPH-binding domains. c.732-2A&amp;gt;T and c.1249-2A&amp;gt;C skipped exons 8 and 12, which altered FAD-binding site conformation. c.1249-2A&amp;gt;C mRNA reduction was not rescued by cycloheximide, arguing against NMD and suggesting nuclear retention or intranuclear decay. We classified two variants as pathogenic (c.731\u00a0+\u00a01G&amp;gt;A, c.947\u00a0+\u00a01G&amp;gt;A), two as likely pathogenic (c.732-2A&amp;gt;T and the novel c.1249-2A&amp;gt;C), and one as likely benign (c.948-30G&amp;gt;A).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings establish that\n                      <jats:italic>POR<\/jats:italic>\n                      splicing variants, whether causing exon skipping or intron retention, disrupt essential domains and produce severe disease. Minigene-based functional testing enables precise variant classification and sharpens genotype-phenotype correlations, supporting improved diagnosis and informed genetic counseling.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1807069","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T04:27:46Z","timestamp":1777264066000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional and structural characterization of POR splicing variants reveals pathogenic mechanisms in PORD"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin Jie","family":"Zhang","sequence":"first","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, China"]},{"name":"Tianjin Pediatric Research Institute","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Birth Defects for Prevention and Treatment","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital","place":["Beijing, China"]},{"name":"Graduate College of Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao Wei","family":"Xu","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, China"]},{"name":"Tianjin Pediatric Research Institute","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Birth Defects for Prevention and Treatment","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, China"]},{"name":"Tianjin Pediatric Research Institute","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Birth Defects for Prevention and Treatment","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Qian","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, China"]},{"name":"Department of Endocrinology, Children\u2019s Hospital, Tianjin University\/Tianjin Children's Hospital","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao Yu","family":"Gong","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, China"]},{"name":"Tianjin Pediatric Research Institute","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Birth Defects for Prevention and Treatment","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen Chao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian Bo","family":"Shu","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, China"]},{"name":"Tianjin Pediatric Research Institute","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Birth Defects for Prevention and Treatment","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun Quan","family":"Cai","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Tianjin University\/Tianjin Children\u2019s Hospital","place":["Tianjin, 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