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

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.

Evaluation of cytotoxic T-cell activation, chemokine receptors, and adhesion molecules in blood and serum in patients with oral lichen planus.

BACKGROUND: Our purpose is to study cytotoxic T-cell activation (through evaluation of CD8+CD40+ and CD8+CD154+ cells), chemokine receptors (through evaluation of CD8+CD184+ and CD8+CD195+ cells), and adhesion molecules (through evaluation of CD8+CD152+ cells) which play a part in cell activation in blood and serum samples of patients with OLP and then to compare them with healthy controls. METHODS: Thirty patients with OLP, and 30 matched healthy controls participated. The mean ages of OLP patients and controls were 51,10 ± 12,25 and 48,09 ± 11,92, respectively. Percentage of apoptotic cells, granzyme-B+, CD8+, CD8+CD40+, CD8+CD152+ (CTLA-4), CD8+CD154+(CD40L), CD8+CD184+(CXCR-4) and CD8+CD195+(CCR-5) were detected by immunophenotyping on flow cytometry. Apoptosis measurements were accomplished with Annexin V/Propidium Iodide kit. RESULTS: A higher percentage of CD8+CD154+ and granzyme-B+ and a lower percentage of CD8+, CD8+CD184+ and apoptotic cells were found in OLP patients than in controls. No statistical differences were observed in the percentages of the other markers between groups. CONCLUSIONS: It is observed that because of increase in granzyme B+ and CD154 which is the activation marker, CD8+ cells present efforts to sustain their activity even though decrease in their cell number. Lower levels of CD8+CD184+ cells in OLP than control is evaluated as a factor that makes OLP to be localised in our study. In addition, our findings lead us to think that there may be some changes in apoptosis pathways of the cells. But this needs to be clarified by further studies exploring the mechanisms of the apoptosis in OLP patients.