Abstract
U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an indispensable pre-mRNA splicing factor in the early process of splicing. Recently, U2AF2 was reported as a novel candidate gene associated with neurodevelopmental disorders. Herein, we report a patient with a novel presumed heterozygous missense variant in the U2AF2 gene (c.603G>T), who has a similar clinical phenotype as the patient reported before, including epilepsy, intellectual disability, language delay, microcephaly, and hypoplastic corpus callosum. We reviewed the phenotypic and genetic spectrum of patients with U2AF2-related neurological diseases, both newly diagnosed and previously reported. To investigate the possible pathogenesis, EBV-immortalized lymphoblastoid cells were derived from the peripheral blood obtained from the patient and control groups. Furthermore, according to the results of WB, RT-PCR, Q-PCR, and cDNA sequencing of RT-PCR products, the presumed missense variant c.603G>T caused exon 6 skipping in the U2AF2 mRNA transcript and led to a truncated protein (p.E163_E201del). Cell Counting Kit-8 (CCK-8) and cell cycle detection demonstrated that the variant c.603G>T inhibited the proliferation of patient lymphocyte cells compared with the control group. This study is aimed at expanding the phenotypic and genetic spectrum of U2AF2-related neurodevelopmental diseases and investigating the potential effects. This is the first report of the possible pathogenesis of a U2AF2 gene pathogenic variant in a patient with neurodevelopmental diseases and shows that a novel presumed missense variant in the U2AF2 gene causes exon skipping.
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Acknowledgements
We are grateful to the patient and his parents for their participation in this study. We thank Guizhi Tang (Hunan Key Laboratory of Medical Genetics, Central South University, China) for helping immortalize lymphocytes.
Funding
This work was supported by the National Natural Science Foundation of China (82071462, 81771409), the Natural Science Foundation of Hunan Province (2021JJ40969), and the Epilepsy Research Foundation of the China Association Against Epilepsy (CX-A-2021-17).
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Conceptualization: XW and JP; investigation: XW, HH, and XN; formal analysis: XW, BY, FL, and NP; resources: XW, CC, and ZP; writing—original draft preparation: XW; writing—review, and editing: JP. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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10038_2023_1128_MOESM2_ESM.docx
Supplementary Information 2. The evolutionary conservation of the E201D mutation in the U2AF2 gene among humans and various vertebrates
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Wang, X., You, B., Yin, F. et al. A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases. J Hum Genet 68, 375–382 (2023). https://doi.org/10.1038/s10038-023-01128-2
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DOI: https://doi.org/10.1038/s10038-023-01128-2
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