{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:10:28Z","timestamp":1784005828737,"version":"3.55.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"5","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,5]]},"abstract":"\nContext<\/jats:title>\nMost of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C<\/jats:italic> gene. This gene encodes B\u2033gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine\/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C<\/jats:italic> gene is most abundantly expressed in testis in humans, while its function was hitherto unknown.<\/jats:p>\n<\/jats:sec>\n\nPatients and methods<\/jats:title>\nFour girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C<\/jats:italic> gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics.<\/jats:p>\n<\/jats:sec>\n\nResults<\/jats:title>\nWe have identified three different homozygous PPP2R3C<\/jats:italic> variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C<\/jats:italic> variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility.<\/jats:p>\n<\/jats:sec>\n\nConclusion<\/jats:title>\nOur findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-19-0067","type":"journal-article","created":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T15:46:16Z","timestamp":1553096776000},"page":"291-309","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":26,"title":["PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans"],"prefix":"10.1093","volume":"180","author":[{"given":"Tulay","family":"Guran","sequence":"first","affiliation":[{"name":"1Department of Paediatric Endocrinology and Diabetes, Marmara University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gozde","family":"Yesil","sequence":"additional","affiliation":[{"name":"2Department of Genetics, Bezm-i Alem University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serap","family":"Turan","sequence":"additional","affiliation":[{"name":"1Department of Paediatric Endocrinology and Diabetes, Marmara University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"Atay","sequence":"additional","affiliation":[{"name":"3Department of Paediatric Endocrinology and Diabetes, Medipol University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emine","family":"Bozkurtlar","sequence":"additional","affiliation":[{"name":"4Department of Pathology, Marmara University, School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AghaRza","family":"Aghayev","sequence":"additional","affiliation":[{"name":"5Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinem","family":"Gul","sequence":"additional","affiliation":[{"name":"6Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilker","family":"Tinay","sequence":"additional","affiliation":[{"name":"7Department of Urology, Marmara University, School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basak","family":"Aru","sequence":"additional","affiliation":[{"name":"8Department of Immunology, Yeditepe University, Faculty of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sema","family":"Arslan","sequence":"additional","affiliation":[{"name":"9Department of Biochemistry, Genetic and Metabolic Diseases Research and Investigation Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Kutay","family":"Koroglu","sequence":"additional","affiliation":[{"name":"10Department of Histology and Embryology, Marmara University, School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feriha","family":"Ercan","sequence":"additional","affiliation":[{"name":"10Department of Histology and Embryology, Marmara University, School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulderen Y","family":"Demirel","sequence":"additional","affiliation":[{"name":"8Department of Immunology, Yeditepe University, Faculty of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Funda S","family":"Eren","sequence":"additional","affiliation":[{"name":"4Department of Pathology, Marmara University, School of Medicine, Istanbul, 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