Pla2g4c-KO Mouse

Pla2g4c, encoding cytosolic phospholipase A2-gamma (cPLA2-γ), is a gene located on chromosome 19q13.3 [3]. The enzyme it encodes catalyzes the release of certain fatty acids from phospholipids, playing roles in physiological functions such as cell membrane remodeling, prostaglandin production, and lipid droplet (LD) formation [7,6]. It is also involved in the arachidonic acid metabolism pathway [2].

Genome-wide association studies have linked Pla2g4c to multiple system atrophy. The rs2303744 polymorphism leads to an amino acid substitution in cPLA2-γ, with the MSA risk allele-encoded cPLA2γ-Ile143 isoform having decreased transacylase activity, which may perturb membrane phospholipids and α-synuclein biology [1]. In an experimental asthma model, the Pla2g4c/Ptgs2/Hpgds axis was augmented in bronchial smooth muscle tissues, suggesting a role in asthma-related airway hyperresponsiveness [2]. Polymorphisms in Pla2g4c have also been associated with schizophrenia risk and illness severity in a Croatian population, and with autism spectrum disorder in the Northeast Han Chinese population [5,8]. Additionally, it may have a role in hepatitis C virus replication, glioma 19q loss detection, and as a prognostic biomarker in stage II colorectal cancer [4,3,7].

In conclusion, Pla2g4c is crucial for various physiological and pathological processes. Studies on its polymorphisms and gene-associated functions in different populations and disease models have enhanced our understanding of its roles in multiple system atrophy, asthma, schizophrenia, autism, hepatitis C virus replication, glioma, and colorectal cancer prognosis. These findings contribute to the exploration of potential diagnostic and therapeutic targets related to Pla2g4c-associated diseases.

References:

1. Nakahara, Yasuo, Mitsui, Jun, Date, Hidetoshi, Foroud, Tatiana, Tsuji, Shoji. 2023. Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy. In medRxiv : the preprint server for health sciences, , . doi:10.1101/2023.05.02.23289328. https://pubmed.ncbi.nlm.nih.gov/37425910/

2. Chiba, Yoshihiko, Suto, Wataru, Sakai, Hiroyasu. 2018. Augmented Pla2g4c/Ptgs2/Hpgds axis in bronchial smooth muscle tissues of experimental asthma. In PloS one, 13, e0202623. doi:10.1371/journal.pone.0202623. https://pubmed.ncbi.nlm.nih.gov/30161143/

3. Hartmann, Christian, Johnk, Loki, Sasaki, Hikaru, Jenkins, Robert B, Louis, David N. . Novel PLA2G4C polymorphism as a molecular diagnostic assay for 19q loss in human gliomas. In Brain pathology (Zurich, Switzerland), 12, 178-82. doi:. https://pubmed.ncbi.nlm.nih.gov/11958371/

4. Mishchenko, E L, Makarova, A A, Antropova, E A, Demenkov, P S, Ivanisenko, V A. . Molecular-genetic pathways of hepatitis C virus regulation of the expression of cellular factors PREB and PLA2G4C, which play an important role in virus replication. In Vavilovskii zhurnal genetiki i selektsii, 27, 776-783. doi:10.18699/VJGB-23-90. https://pubmed.ncbi.nlm.nih.gov/38213698/

5. Nadalin, Sergej, Buretić-Tomljanović, Alena. 2017. An association between PLA2G6 and PLA2G4C gene polymorphisms and schizophrenia risk and illness severity in a Croatian population. In Prostaglandins, leukotrienes, and essential fatty acids, 121, 57-59. doi:10.1016/j.plefa.2017.06.003. https://pubmed.ncbi.nlm.nih.gov/28651698/

6. Su, Xi, Liu, Shuhui, Zhang, Xianwen, Pei, Rongjuan, Chen, Xinwen. 2017. Requirement of cytosolic phospholipase A2 gamma in lipid droplet formation. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1862, 692-705. doi:10.1016/j.bbalip.2017.03.007. https://pubmed.ncbi.nlm.nih.gov/28336330/

7. Olsen, Renate S, Andersson, Roland E, Zar, Niklas, Matussek, Andreas, Dimberg, Jan. 2015. Prognostic significance of PLA2G4C gene polymorphism in patients with stage II colorectal cancer. In Acta oncologica (Stockholm, Sweden), 55, 474-9. doi:10.3109/0284186X.2015.1073350. https://pubmed.ncbi.nlm.nih.gov/26364726/

8. Liu, Shicheng, Qiu, Shuang, Lu, Yuping, Liu, Yawen, Jiang, Huiyi. 2016. The rs251684 Variant of PLA2G4C Is Associated with Autism Spectrum Disorder in the Northeast Han Chinese Population. In Genetic testing and molecular biomarkers, 20, 747-752. doi:10.1089/gtmb.2016.0195. https://pubmed.ncbi.nlm.nih.gov/27611910/