机构：[1]Department of Neurology, Xiangya Hospital, Central South University, 410008 Changsha, Hunan, China.[2]Center for Medical Genetics, School of Life Sciences, Central South University, 410078 Changsha, China.[3]National Clinical Research Center for Geriatric Disorders, Central South University, 410008 Changsha, Hunan, China.[4]Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, 410008 Changsha, Hunan, China.[5]Department of Computer Science, Stanford University, Stanford, CA 94305.[6]Department of Pathology, Stanford University, Stanford, CA 94305.[7]Department of Computer Science, City University of Hong Kong, Kowloon, Hong Kong Special Administrative Region, China.[8]Network Information Center, Xiangya Hospital, Central South University, 410008 Changsha, Hunan, China.[9]Department of Neurobiology, Xuanwu Hospital of Capital Medical University, 100053 Beijing, China.首都医科大学宣武医院[10]Parkinson's Disease Center, Beijing Institute for Brain Disorders, 100101 Beijing, China.[11]Department of Neurology, West China Hospital, Sichuan University, 61004 Chengdu, Sichuan, China.[12]Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China.[13]Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 310009 Zhejiang, China.[14]Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China.[15]Center for Human Genome Research, Huazhong University of Science and Technology, 430074 Wuhan, Hubei, China.[16]Department of Pharmacology, Soochow University, College of Pharmaceutical Sciences, 215021 Suzhou, China.[17]Division of Clinical Sciences, Lieber Institute for Brain Development, John Hopkins University Medical Campus, Baltimore, MD 21205.[18]Collaborative Innovation Center for Genetics and Development, 200433 Shanghai, China.[19]Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60607.[20]Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.[21]Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.[22]Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.[23]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.[24]Collaborative Innovation Center for Brain Science, 200433 Shanghai, China.
Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.
基金：
This work was supported by National Key Plan for Scientific
Research and Development of China Grant 2016YFC1306000 and National
Natural Science Foundation of China Grant 81430023.
第一作者机构：[1]Department of Neurology, Xiangya Hospital, Central South University, 410008 Changsha, Hunan, China.[2]Center for Medical Genetics, School of Life Sciences, Central South University, 410078 Changsha, China.[3]National Clinical Research Center for Geriatric Disorders, Central South University, 410008 Changsha, Hunan, China.[4]Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, 410008 Changsha, Hunan, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurology, Xiangya Hospital, Central South University, 410008 Changsha, Hunan, China.[2]Center for Medical Genetics, School of Life Sciences, Central South University, 410078 Changsha, China.[3]National Clinical Research Center for Geriatric Disorders, Central South University, 410008 Changsha, Hunan, China.[4]Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, 410008 Changsha, Hunan, China.[10]Parkinson's Disease Center, Beijing Institute for Brain Disorders, 100101 Beijing, China.[18]Collaborative Innovation Center for Genetics and Development, 200433 Shanghai, China.[24]Collaborative Innovation Center for Brain Science, 200433 Shanghai, China.
推荐引用方式(GB/T 7714)：
Guo Ji-Feng,Zhang Lu,Li Kai,et al.Coding mutations in NUS1 contribute to Parkinson's disease[J].PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA.2018,115(45):11567-11572.doi:10.1073/pnas.1809969115.
APA：
Guo, Ji-Feng,Zhang, Lu,Li, Kai,Mei, Jun-Pu,Xue, Jin...&Tang, Bei-Sha.(2018).Coding mutations in NUS1 contribute to Parkinson's disease.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,115,(45)
MLA：
Guo, Ji-Feng,et al."Coding mutations in NUS1 contribute to Parkinson's disease".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115..45(2018):11567-11572
综合性期刊