Ppp1r3f-KO Mouse

Ppp1r3f, encoding protein phosphatase 1 regulatory subunit 3F, is a member of the glycogen targeting subunits (GTSs) of protein phosphatase 1 (PP1). PP1 is a major eukaryotic serine/threonine protein phosphatase regulating diverse cellular processes. Ppp1r3f is involved in maintaining brain glycogen levels and is associated with pathways related to neurodevelopment [1,5].

Hemizygous variants in PPP1R3F are associated with an X-linked recessive neurodevelopmental disorder characterized by developmental delay, intellectual disability, autistic features, seizures, and other neurological abnormalities [1]. Functional studies on identified variants showed defects in PP1 binding, protein stability, subcellular localization, and regulation of glycogen metabolism [1]. PPP1R3F knockout astrocytoma cells have more sensitive glycogen content to extracellular glucose level changes, suggesting its role in maintaining steady brain glycogen levels [1]. In addition, PPP1R3F has been studied in relation to autism spectrum disorders (ASDs), with transcriptional network analysis identifying it as a candidate master regulator affecting downstream genes associated with the disease phenotype, and pathway analysis indicating alteration of the endocytosis pathway [3]. Also, non-synonymous rare variants in PPP1R3F were identified in individuals with ASD in a study sequencing X-linked synaptic genes [4]. Moreover, the hypermethylation of PPP1R3F in blood leukocytes is related to an increased colorectal cancer risk, and there is a synergistic interaction between its hypermethylation and fried food consumption on CRC risk [2].

In conclusion, Ppp1r3f plays a critical role in maintaining brain glycogen levels and is significantly associated with neurodevelopmental disorders like those with autistic features and intellectual disability. Its involvement in endocytosis pathway in ASDs and association with CRC risk due to hypermethylation highlight its importance in understanding these disease mechanisms. The study of Ppp1r3f through gene-related models helps in uncovering its functions in these specific biological processes and disease conditions [1,2,3,4].

References:

1. Liu, Zhigang, Xin, Baozhong, Smith, Iris N, Zhang, Bin, Wang, Heng. . Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features. In Human molecular genetics, 32, 2981-2995. doi:10.1093/hmg/ddad124. https://pubmed.ncbi.nlm.nih.gov/37531237/

2. Tian, Tian, Bi, Haoran, Zhang, Ding, Zhu, Lin, Zhao, Yashuang. 2021. Methylation of three genes encoded by X chromosome in blood leukocytes and colorectal cancer risk. In Cancer medicine, 10, 4964-4976. doi:10.1002/cam4.4056. https://pubmed.ncbi.nlm.nih.gov/34145793/

3. Doostparast Torshizi, Abolfazl, Duan, Jubao, Wang, Kai. 2018. Transcriptional network analysis on brains reveals a potential regulatory role of PPP1R3F in autism spectrum disorders. In BMC research notes, 11, 489. doi:10.1186/s13104-018-3594-0. https://pubmed.ncbi.nlm.nih.gov/30016992/

4. Piton, A, Gauthier, J, Hamdan, F F, Drapeau, P, Rouleau, G A. 2010. Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. In Molecular psychiatry, 16, 867-80. doi:10.1038/mp.2010.54. https://pubmed.ncbi.nlm.nih.gov/20479760/

5. Kelsall, Ian R, Voss, Martin, Munro, Shonagh, Cuthbertson, Daniel J R, Cohen, Patricia T W. 2011. R3F, a novel membrane-associated glycogen targeting subunit of protein phosphatase 1 regulates glycogen synthase in astrocytoma cells in response to glucose and extracellular signals. In Journal of neurochemistry, 118, 596-610. doi:10.1111/j.1471-4159.2011.07345.x. https://pubmed.ncbi.nlm.nih.gov/21668450/