Heterozygous variants in USP25 cause genetic generalized epilepsy
文献类型：期刊论文
| 作者 | Fan, Cui-Xia5,6; Liu, Xiao-Rong5,6; Mei, Dao-Qi4; Li, Bing-Mei5,6; Li, Wen-Bin5,6; Xie, Huan-Cheng5,6; Wang, Jie5,6; Shen, Nan-Xiang5,6; Ye, Zi-Long5,6; You, Qiang-Long5,6 |
| 刊名 | BRAIN
 |
| 出版日期 | 2024-08-23 |
| 页码 | 16 |
| 关键词 | genetic generalized epilepsy USP25 gain of function loss of function |
| ISSN号 | 0006-8950 |
| DOI | 10.1093/brain/awae191 |
| 通讯作者 | Chen, Qian(chenqian@zidd.ac.cn) ; Shi, Yi-Wu(stoneyiwu@163.com) |
| 英文摘要 | USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined.In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown aetiology. Five heterozygous USP25 variants, including two de novo and three co-segregated variants, were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared with the East Asian population and all populations in the gnomAD database. The mean age at onset of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom, except that one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability.Usp25 was expressed ubiquitously in mouse brain with two peaks, on embryonic Days 14-16 and postnatal Day 21, respectively. In human brain, likewise, USP25 is expressed in the fetus/early childhood stage and with a second peak at similar to 12-20 years old, consistent with the seizure onset age in patients during infancy and in juveniles.To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knockout mice, which showed increased seizure susceptibility compared with wild-type mice in a pentylenetetrazol-induced seizure test.To explore the impact of USP25 variants, we used multiple functional detections. In HEK293 T cells, the variant associated with a severe phenotype (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed stable truncated dimers with an increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del variants increased neuronal excitability in mouse brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating that USP25 is potentially a predisposing gene for epilepsy.Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play an epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have a profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain. Fan et al. perform trio-based whole exome sequencing in a cohort of individuals with idiopathic generalized epilepsy, and identify five variants in USP25 in eight individuals. By studying the variants in vitro and in vivo, they obtain comprehensive evidence that the variants cause a form of generalized epilepsy with dominant inheritance. |
| WOS关键词 | LOSS-OF-FUNCTION ; INTELLECTUAL DISABILITY ; FUNCTION MUTATIONS ; ILAE COMMISSION ; UBIQUITIN ; CLASSIFICATION ; SUBUNIT ; REGION ; USP9X |
| 资助项目 | National Natural Science Foundation of China[82171439] ; National Natural Science Foundation of China[82271505] ; National Natural Science Foundation of China[82201602] ; National Natural Science Foundation of China[82201609] ; National Natural Science Foundation of China[82271578] ; Guangdong Basic and Applied Basic Research Foundation[2021A1515010986] ; Guangdong Basic and Applied Basic Research Foundation[2021A1515110792] ; Technology Project of Guangzhou[201904020028] ; Guangzhou Science and Technology Program City-University Joint Funding Project[2023A03J0412] ; CAAE Epilepsy Research fund-UCB[CU-2023-003] |
| WOS研究方向 | Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:001296119900001 |
| 出版者 | OXFORD UNIV PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/312884]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Qian; Shi, Yi-Wu |
| 作者单位 | 1.Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Chinese Acad Sci, Zhongshan 528400, Peoples R China 2.Fourth Mil Med Univ, Sch Basic Med, Dept Neurobiol, Xian 710032, Peoples R China 3.Guangzhou Med Univ, Dept Stomatol Affiliated Hosp 2, Guangzhou 510260, Peoples R China 4.Childrens Hosp Soochow Univ, Dept Neurol, Suzhou 215000, Peoples R China 5.Guangzhou Med Univ Chang gang, Affiliated Hosp 2, Minist Educ China, dong Rd 250, Guangzhou 510260, Peoples R China 6.Guangzhou Med Univ Chang gang, Inst Neurosci, Dept Neurol, Key Lab Neurogenet & Channelopathies Guangdong Pro, Guangzhou 510260, Peoples R China |
| 推荐引用方式 GB/T 7714 | Fan, Cui-Xia,Liu, Xiao-Rong,Mei, Dao-Qi,et al. Heterozygous variants in USP25 cause genetic generalized epilepsy[J]. BRAIN,2024:16. |
| APA | Fan, Cui-Xia.,Liu, Xiao-Rong.,Mei, Dao-Qi.,Li, Bing-Mei.,Li, Wen-Bin.,...&Shi, Yi-Wu.(2024).Heterozygous variants in USP25 cause genetic generalized epilepsy.BRAIN,16. |
| MLA | Fan, Cui-Xia,et al."Heterozygous variants in USP25 cause genetic generalized epilepsy".BRAIN (2024):16. |
入库方式： OAI收割
来源：上海药物研究所
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