U2af2, also known as U2 small nuclear RNA auxiliary factor 2, is an indispensable pre-mRNA splicing factor in the early splicing process. It plays a crucial role in ensuring splicing fidelity by selecting the intronic polypyrimidine sequence of premature mRNA [1,5,7]. The U2AF1/U2AF2 heterodimer is critical for 3' splice site (3'SS) definition [8]. This function is essential for normal gene expression and is involved in various biological processes such as neural development and cell proliferation.

In neurodevelopmental diseases, a presumed missense variant (c.603G>T) in the U2AF2 gene has been reported to cause exon 6 skipping in the U2AF2 mRNA transcript, leading to a truncated protein (p.E163_E201del) and inhibiting the proliferation of patient lymphocyte cells. This expands the phenotypic and genetic spectrum of U2AF2-related neurodevelopmental diseases [1]. Additionally, variants in U2AF2 are hypothesized to cause a novel neurodevelopmental disorder, with patients showing features like global developmental delay, dysmorphic features, and epilepsy [2]. In Drosophila, neural loss-of-function of the ortholog U2af50 led to lethality, abnormal mushroom body patterning, and social deficits, which helps understand the role of U2af2 in neural development [4]. In triple-negative breast cancer, U2AF2-SNORA68 promotes cancer stemness by retaining RPL23 in the nucleolus and increasing c-Myc expression [3]. In glioma stem cells, U2AF2 is part of a feedback loop (U2AF2 /circRNA ARF1/miR-342-3p/ISL2) that regulates angiogenesis [6].

In conclusion, U2af2 is essential for pre-mRNA splicing, which is fundamental to normal biological function. Studies, including those using model organisms like Drosophila, have revealed its significance in neurodevelopmental diseases, breast cancer, and glioma angiogenesis. Understanding U2af2's function provides insights into the pathogenesis of these diseases and may offer potential therapeutic targets.

References:

1. Wang, Xiaole, You, Baiyang, Yin, Fei, Pang, Nan, Peng, Jing. 2023. A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases. In Journal of human genetics, 68, 375-382. doi:10.1038/s10038-023-01128-2. https://pubmed.ncbi.nlm.nih.gov/36747105/

2. Kittock, Claire M, Saifeddine, Mohamad, Straight, Lisa, Ward, D Isum. 2023. U2AF2 variant in a patient with developmental delay, dysmorphic features, and epilepsy. In American journal of medical genetics. Part A, 191, 1968-1972. doi:10.1002/ajmg.a.63221. https://pubmed.ncbi.nlm.nih.gov/37092751/

3. Zhang, Wenrong, Song, Xinyue, Jin, Zining, Jin, Feng, Zheng, Ang. 2024. U2AF2-SNORA68 promotes triple-negative breast cancer stemness through the translocation of RPL23 from nucleoplasm to nucleolus and c-Myc expression. In Breast cancer research : BCR, 26, 60. doi:10.1186/s13058-024-01817-6. https://pubmed.ncbi.nlm.nih.gov/38594783/

4. Li, Dong, Wang, Qin, Bayat, Allan, Song, Yuanquan, Hakonarson, Hakon. 2024. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features. In The Journal of clinical investigation, 134, . doi:10.1172/JCI171235. https://pubmed.ncbi.nlm.nih.gov/37962958/

5. Maji, Debanjana, Glasser, Eliezra, Henderson, Steven, Jenkins, Jermaine L, Kielkopf, Clara L. 2020. Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing. In The Journal of biological chemistry, 295, 17148-17157. doi:10.1074/jbc.RA120.015339. https://pubmed.ncbi.nlm.nih.gov/33020180/

6. Jiang, Yang, Zhou, Jinpeng, Zhao, Junshuang, Zheng, Wei, Jing, Zhitao. 2020. The U2AF2 /circRNA ARF1/miR-342-3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells. In Journal of experimental & clinical cancer research : CR, 39, 182. doi:10.1186/s13046-020-01691-y. https://pubmed.ncbi.nlm.nih.gov/32894165/

7. Rozza, Riccardo, Saltalamacchia, Andrea, Orrico, Clarissa, Janoš, Pavel, Magistrato, Alessandra. 2022. All-Atom Simulations Elucidate the Impact of U2AF2 Cancer-Associated Mutations on Pre-mRNA Recognition. In Journal of chemical information and modeling, 62, 6691-6703. doi:10.1021/acs.jcim.2c00511. https://pubmed.ncbi.nlm.nih.gov/36040856/

8. Biancon, Giulia, Joshi, Poorval, Zimmer, Joshua T, Tebaldi, Toma, Halene, Stephanie. . Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. In Molecular cell, 82, 1107-1122.e7. doi:10.1016/j.molcel.2022.02.025. https://pubmed.ncbi.nlm.nih.gov/35303483/