文献类型：期刊文献

英文题名：A novel in-frame deletion in KIF5C gene causes infantile onset epilepsy and psychomotor retardation

作者：Banerjee, Santasree[1,2,3,4];Zhao, Qiang[1,2];Wang, Bo[5];Qin, Jiale[1,2];Yuan, Xin[1,2];Lou, Ziwei[1,2];Zheng, Weizeng[6];Li, Huanguo[7];Wang, Xiaojun[8,9];Cheng, Xiawei[10];Zhu, Yu[8,9];Lin, Fan[11];Yang, Fan[1,2];Xu, Junyu[8,9];Munshi, Anjana[12];Das, Parimal[13];Zhou, Yuanfeng[14,15];Mandal, Kausik[16];Wang, Yi[14,15];Ayub, Muhammad[17];Hirokawa, Nobutaka[18];Xi, Yongmei[1,2,20,21];Chen, Guangfu[5];Li, Chen[1,2,19,20,21]

机构：[1]Zhejiang Univ, Womens Hosp, Sch Basic Med Sci, Sch Med,Dept Human Genet, Hangzhou, Peoples R China;[2]Zhejiang Univ, Womens Hosp, Sch Basic Med Sci, Sch Med,Dept Ultrasound,Zhejiang Prov Key Lab Gene, Hangzhou, Peoples R China;[3]Jilin Univ, Coll Basic Med Sci, Dept Genet, Changchun, Peoples R China;[4]Univ Delhi, Dept Genet, New Delhi, India;[5]Shenzhen Univ, Shenzhen Peoples Hosp 2, Affiliated Hosp 1, Dept Pediat,Hlth Sci Ctr, Shenzhen 518025, Peoples R China;[6]Zhejiang Univ, Womens Hosp, Sch Med, Dept Radiol, Hangzhou, Peoples R China;[7]Hangzhou Hosp Tradit Chinese Med, Dept Radiol, Hangzhou, Peoples R China;[8]Zhejiang Univ, Natl Clin Res Ctr Child Hlth, Sch Med, Dept Neurobiol,Dept Rehabil, Hangzhou, Peoples R China;[9]Zhejiang Univ, Natl Clin Res Ctr Child Hlth, Sch Med, Childrens Hosp,Dept Internal Med, Hangzhou, Peoples R China;[10]East China Univ Sci & Technol, Sch Pharm, Shanghai, Peoples R China;[11]Nanjing Med Univ, Sch Basic Med Sci, Dept Cell Biol, Nanjing, Peoples R China;[12]Cent Univ Punjab, Dept Human Genet & Mol Med, Bathinda, India;[13]Banaras Hindu Univ, Ctr Genet Disorders, Varanasi, India;[14]Fudan Univ, Childrens Hosp, Dept Neurol, Shanghai, Peoples R China;[15]Fudan Univ, Childrens Hosp, Epilepsy Ctr, Shanghai, Peoples R China;[16]Sanjay Gandhi Postgrad Inst Med Sci, Dept Med Genet, Lucknow, Uttar Pradesh, India;[17]UCL, Dept Psychiat, London, England;[18]Univ Tokyo, Grad Sch Med, Dept Cell Biol & Anat, 7-3-1 Hongo,Bunkyo Ku, Tokyo 1130033, Japan;[19]Alibaba Zhejiang Univ, Joint Res Ctr Future Digital Healthcare, Hangzhou, Peoples R China;[20]Zhejiang Univ, Sch Med, Dept Human Genet, Hangzhou 311121, Peoples R China;[21]Zhejiang Univ, Womens Hosp, Sch Med, Hangzhou 311121, Peoples R China

年份：2024

卷号：5

期号：4

外文期刊名：MEDCOMM

收录：WOS:【ESCI(收录号:WOS:001189407100001)】；

基金：We are grateful to all the clinicians and families for their contributions. We would like to thank all anonymous reviewers for their insightful comments. We thank Dr. Min-Xin Guan at Zhejiang University for helpful suggestions. We thank Dr. Fang Xu for the insightful discussions. We would like to thank Ying Liang, Yuyi Ying, Zizhen Xu, Ying Meng, Xialian Weng, and Gongxin Han for their contributions to data analysis, curation, and methodology. We also thank Prof. Xiaohang Yang, Qiming Sun, Baohui Chen, Dante Neculai, and Hai Huang for their contributions to project administration, methodology, writing, and editing of the original draft. We thank Zhaoxiaonan Lin, Jiajia Wang and Chun Guo from the Core Facilities, Zhejiang University School of Medicine for their technical support. We are grateful to Dr. Hangjun Wu in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University for his technical assistance on computer clustering. This work was supported by the research grants from the National Natural Science Foundation of China (82272126 and 82171939), a Joint Project of Science Research of National Health Commission and Zhejiang Province (WKJ-ZJ-2033), Pioneer and Leading Goose R&D Program of Zhejiang (2023C03G1753905[JQ]); National Key Research and Development Program of China (2023YFC2705801[JQ]), Medical Health Science and Technology Plan of Zhejiang Provincial Health Commission (WKJ-ZJ-2408[JQ]), and Zhejiang Provincial Science Foundation Committee (LY22H180009). Chen Li is supported by Alibaba Cloud.

语种：英文

外文关键词：cargo trafficking; Drosophila model; infantile-onset epilepsy; in-frame deletion; Kinesin; psychomotor retardation

摘要：Motor proteins, encoded by Kinesin superfamily (KIF) genes, are critical for brain development and plasticity. Increasing studies reported KIF's roles in neurodevelopmental disorders. Here, a 6 years and 3 months-old Chinese boy with markedly symptomatic epilepsy, intellectual disability, brain atrophy, and psychomotor retardation was investigated. His parents and younger sister were phenotypically normal and had no disease-related family history. Whole exome sequencing identified a novel heterozygous in-frame deletion (c.265_267delTCA) in exon 3 of the KIF5C in the proband, resulting in the removal of evolutionarily highly conserved p.Ser90, located in its ATP-binding domain. Sanger sequencing excluded the proband's parents and family members from harboring this variant. The activity of ATP hydrolysis in vitro was significantly reduced as predicted. Immunofluorescence studies showed wild-type KIF5C was widely distributed throughout the cytoplasm, while mutant KIF5C was colocalized with microtubules. The live-cell imaging of the cargo-trafficking assay revealed that mutant KIF5C lost the peroxisome-transporting ability. Drosophila models also confirmed p.Ser90del's essential role in nervous system development. This study emphasized the importance of the KIF5C gene in intracellular cargo-transport as well as germline variants that lead to neurodevelopmental disorders and might enable clinicians for timely and accurate diagnosis and disease management in the future. We identified a novel heterozygous in-frame deletion (c.265_267delTCA) in exon 3 of KIF5C in a 6 years and 3 months-old Chinese boy with markedly symptomatic epilepsy, intellectual disability, and psychomotor retardation, resulting in the removal of evolutionarily highly conserved p.Ser90 in its ATP-binding domain. This study emphasized the importance of the KIF5C in intracellular cargo-transport as well as germline variants leading to neurodevelopmental disorders. # image