Ppp2r3c, encoding the B″gamma regulatory subunit of protein phosphatase 2A (PP2A), is a serine/threonine phosphatase involved in phospho-regulation processes in most mammalian cell types [3]. It has key functions in centrosome function, as part of a phospho-regulatory module with MAP3K1, and is also associated with the Hedgehog signaling pathway and P-glycoprotein regulation [1,5,4]. It is highly expressed in the testis and is crucial for normal development [3].

Functional genomic analyses and gene-knockout-related evidence show its significance. In mouse models, homozygous Ppp2r3c knockout embryos die from 7.5 days post coitum or earlier, indicating its essential role in mouse development [7]. In humans, inactivating Ppp2r3c mutations cause congenital syndromes characterized by gonadal dysgenesis, affecting both 46,XY and 46,XX individuals [2,6,7]. These mutations also lead to a spectrum of extragonadal anomalies [3,6]. A syndromic Ppp2r3c variant shows defective centriolar localization and binding to centriolar protein FOP, suggesting imbalanced MAP3K1-Ppp2r3c activity causes these disorders [1].

In conclusion, Ppp2r3c is essential for normal development, with its function in the centrosomal phospho-regulatory module being crucial. Studies using gene-knockout models in mice have revealed its role in embryonic viability, and in humans, its inactivation is linked to gonadal dysgenesis and associated syndromes. This understanding provides insights into the pathophysiology of related diseases and potential therapeutic targets.

References:

1. Ganga, Anil Kumar, Sweeney, Lauren K, Rubio Ramos, Armando, Guichard, Paul, Breslow, David K. 2024. A disease-associated PPP2R3C-MAP3K1 phospho-regulatory module controls centrosome function. In Current biology : CB, 34, 4824-4834.e6. doi:10.1016/j.cub.2024.08.058. https://pubmed.ncbi.nlm.nih.gov/39317195/

2. Altunoglu, Umut, Börklü, Esra, Shukla, Anju, Kennerknecht, Ingo, Kayserili, Hülya. 2021. Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis. In Clinical genetics, 101, 221-232. doi:10.1111/cge.14086. https://pubmed.ncbi.nlm.nih.gov/34750818/

3. Guran, Tulay, Yesil, Gozde, Turan, Serap, Karademir, Betul, Bereket, Abdullah. . PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans. In European journal of endocrinology, 180, 291-309. doi:10.1530/EJE-19-0067. https://pubmed.ncbi.nlm.nih.gov/30893644/

4. Katayama, Kazuhiro, Yamaguchi, Miho, Noguchi, Kohji, Sugimoto, Yoshikazu. 2013. Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function. In Cancer letters, 345, 124-31. doi:10.1016/j.canlet.2013.12.007. https://pubmed.ncbi.nlm.nih.gov/24333728/

5. Baran, Brygida, Derua, Rita, Janssens, Veerle, Niewiadomski, Paweł. 2024. PP2A phosphatase regulatory subunit PPP2R3C is a new positive regulator of the hedgehog signaling pathway. In Cellular signalling, 123, 111352. doi:10.1016/j.cellsig.2024.111352. https://pubmed.ncbi.nlm.nih.gov/39173855/

6. Zhang, Wei, Mao, Jiangfeng, Wang, Xi, Nie, Min, Wu, Xueyan. 2022. Case Report: Novel Compound Heterozygotic Variants in PPP2R3C Gene Causing Syndromic 46, XY Gonadal Dysgenesis and Literature Review. In Frontiers in genetics, 13, 871328. doi:10.3389/fgene.2022.871328. https://pubmed.ncbi.nlm.nih.gov/35812758/

7. Cicek, Dilek, Warr, Nick, Yesil, Gozde, Greenfield, Andy, Guran, Tulay. 2021. Broad-spectrum XX and XY gonadal dysgenesis in patients with a homozygous L193S variant in PPP2R3C. In European journal of endocrinology, 186, 65-72. doi:10.1530/EJE-21-0910. https://pubmed.ncbi.nlm.nih.gov/34714774/