Wo-Tu Tian1,2, Fei-Xia Zhan1,2,3, Zhen-Hua Liu2,4, Zhe Liu2,5, Qing Liu2,6, Xia-Nan Guo2,7, Zai-Wei Zhou8, Shi-Ge Wang2,3, Xiao-Rong Liu2,9, Hong Jiang2,4, Xun-Hua Li2,10, Guo-Hua Zhao2,11, Hai-Yan Li2,12, Jian-Guang Tang2,13, Guang-Hui Bi2,14, Ping Zhong2,15, Xiao-Meng Yin2,4, Tao-Tao Liu2,16, Rui-Long Ni2,16, Hao-Ran Zheng2,16, Xiao-Li Liu2,17, Xiao-Hang Qian2,3, Jing-Ying Wu1,2, Yu-Wen Cao1,2, Chao Zhang2,15, Shi-Hua Liu2,15, Ying-Ying Wu2,15, Qun-Feng Wang2,15, Ting Xu2,15, Wen-Zhe Hou2,15, Zi-Yi Li18, Hui-Yi Ke18, Ze-Yu Zhu1,2, Lan Zheng2,19, Tian Wang2,20, Tian-Yi Rong2,21, Li Wu2,22, Yu Zhang2,23, Kan Fang2,24, Zhan-Hang Wang2,25, Ya-Kun Zhang26, Mei Zhang2,16, Yu-Wu Zhao1,2, Bei-Sha Tang2,4, Xing-Hua Luan1,2, Xiao-Jun Huang2,3, Li Cao1,2,15,16. 1. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. 2. China Paroxysmal Dyskinesia Collaborative Group (CPDCG), Shanghai, China. 3. Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 4. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China. 5. Laboratory of Clinical Genetics, Medical Science Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. 6. Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. 7. Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Key Laboratory of Kidney Disease of Liaoning Province, The Center for the Transformation Medicine of Kidney Disease of Liaoning Province, Dalian, China. 8. Shanghai Xunyin Biotechnology Co., Ltd., Shanghai, China. 9. Institute of Neuroscience of The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 10. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 11. Department of Neurology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China. 12. Department of Neurology, Anyang People's Hospital, Anyang, China. 13. Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, China. 14. Department of Neurology, Dongying People's Hospital, Dongying, China. 15. Department of Neurology, Suzhou Hospital of Anhui Medical University, Suzhou, China. 16. Department of Neurology, The First Hospital Affiliated to Anhui University of Science & Technology, Huainan, China. 17. Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China. 18. Shanghai Jiao Tong University School of Medicine, Shanghai, China. 19. Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China. 20. Department of Neurology, The Central Hospital of Wuhan, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China. 21. Department of Neurology, Shidong Hospital of Yangpu District, Shanghai, China. 22. Department of Neurology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 23. Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 24. Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China. 25. Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China. 26. Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract
BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD.
BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD.