• PMID: 30893644
• Gene Name: PPP2R3C
• Condition: 46,XY gonadal dysgenesis and impaired spermatogenesis, Gene crucial for testis development and spermatogenesis
• Association: Associated
• Mutation: c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S)
• Population size: 4
• Population details: 4 girls with 46, XY complete gonadal dysgenesis
• Sex: Male
• Infertility type: Male infertility
• Associated genes: SOX9
• Other associated phenotypes: 46,XY gonadal dysgenesis and impaired spermatogenesis, Gene crucial for testis development and spermatogenesis

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

Guran T, Yesil G, Turan S, Atay Z, Bozkurtlar E, Aghayev A, Gul S, Tinay I, Aru B, Arslan S, Koroglu MK, Ercan F, Demirel GY, Eren FS, Karademir B, Bereket A.

Context Most 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 gene. This gene encodes B″gamma 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 gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C 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 variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our 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. FAU - Guran, Tulay AU - Guran T AD - Department of Paediatric Endocrinology and Diabetes, Marmara University. FAU - Yesil, Gozde AU - Yesil G AD - Department of Genetics, Bezm-i Alem University. FAU - Turan, Serap AU - Turan S AD - Department of Paediatric Endocrinology and Diabetes, Marmara University. FAU - Atay, Zeynep AU - Atay Z AD - Department of Paediatric Endocrinology and Diabetes, Medipol University. FAU - Bozkurtlar, Emine AU - Bozkurtlar E AD - Department of Pathology, Marmara University, School of Medicine, Istanbul, Turkey. FAU - Aghayev, AghaRza AU - Aghayev A AD - Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. FAU - Gul, Sinem AU - Gul S AD - Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli, Turkey. FAU - Tinay, Ilker AU - Tinay I AD - Department of Urology, Marmara University, School of Medicine, Istanbul, Turkey. FAU - Aru, Basak AU - Aru B AD - Department of Immunology, Yeditepe University, Faculty of Medicine, Istanbul, Turkey. FAU - Arslan, Sema AU - Arslan S AD - Department of Biochemistry, Genetic and Metabolic Diseases Research and Investigation Center. FAU - Koroglu, M Kutay AU - Koroglu MK AD - Department of Histology and Embryology, Marmara University, School of Medicine, Istanbul, Turkey. FAU - Ercan, Feriha AU - Ercan F AD - Department of Histology and Embryology, Marmara University, School of Medicine, Istanbul, Turkey. FAU - Demirel, Gulderen Y AU - Demirel GY AD - Department of Immunology, Yeditepe University, Faculty of Medicine, Istanbul, Turkey. FAU - Eren, Funda S AU - Eren FS AD - Department of Pathology, Marmara University, School of Medicine, Istanbul, Turkey. FAU - Karademir, Betul AU - Karademir B AD - Department of Biochemistry, Genetic and Metabolic Diseases Research and Investigation Center.