A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases

• Published in: Journal of human genetics Vol. 68; no. 6; pp. 375 - 382
• Main Authors: Wang, Xiaole, You, Baiyang, Yin, Fei, Chen, Chen, He, Hailan, Liu, Fangyun, Pan, Zou, Ni, Xiaoyuan, Pang, Nan, Peng, Jing
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2023
• Subjects: Cell cycle; Cell proliferation; Cholecystokinin; Corpus callosum; Epilepsy; Exon skipping; Exons - genetics; Humans; Intellectual disabilities; Lymphocytes; Microencephaly; Mutation, Missense; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurological diseases; Pathogenesis; Peripheral blood; Phenotypes; Polymerase chain reaction; Ribonucleoproteins (U2 small nuclear); RNA Splicing - genetics; RNA, Messenger - genetics; snRNA; Splicing Factor U2AF - genetics; Splicing factors
• ISSN: 1434-5161; 1435-232X; 1435-232X
• DOI: 10.1038/s10038-023-01128-2

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.