@article{e169f82d02f54916b4ee0a7b1457ce12,
title = "Coding mutations in NUS1 contribute to Parkinson's disease",
abstract = "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.",
keywords = "De novo mutations, Disease-risk gene, Exome sequencing, Neurodegenerative disorders, Parkinson's disease",
author = "Guo, {Ji Feng} and Lu Zhang and Kai Li and Mei, {Jun Pu} and Jin Xue and Jia Chen and Xia Tang and Lu Shen and Hong Jiang and Chao Chen and Hui Guo and Wu, {Xue Li} and Sun, {Si Long} and Qian Xu and Sun, {Qi Ying} and Piu Chan and Shang, {Hui Fang} and Tao Wang and Zhao, {Guo Hua} and Liu, {Jing Yu} and Xie, {Xue Feng} and Jiang, {Yi Qi} and Liu, {Zhen Hua} and Zhao, {Yu Wen} and Zhu, {Zuo Bin} and Li, {Jia Da} and Hu, {Zheng Mao} and Yan, {Xin Xiang} and Fang, {Xiao Dong} and Wang, {Guang Hui} and Zhang, {Feng Yu} and Kun Xia and Liu, {Chun Yu} and Zhu, {Xiong Wei} and Yue, {Zhen Yu} and Li, {Shuai Cheng} and Cai, {Huai Bin} and Zhang, {Zhuo Hua} and Duan, {Ran Hui} and Tang, {Bei Sha}",
note = "Funding Information: We thank all the patients and family members for their generous participation in this work; BGI-Shenzhen for assistance in exome sequencing and data analysis; Yuanwei Zhang (University of Science and Technology of China) and Jieqiong Tan (School of Life Sciences, Central South University) for their kind help in analyzing the functional impact of splicing mutation; and Prof. Evan E. Eichler for assistance with the data analysis. 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. Funding Information: ACKNOWLEDGMENTS. We thank all the patients and family members for their generous participation in this work; BGI-Shenzhen for assistance in exome sequencing and data analysis; Yuanwei Zhang (University of Science and Technology of China) and Jieqiong Tan (School of Life Sciences, Central South University) for their kind help in analyzing the functional impact of splicing mutation; and Prof. Evan E. Eichler for assistance with the data analysis. 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. Publisher Copyright: {\textcopyright} 2018 BioMed Central Ltd..All right reserved.",
year = "2018",
month = oct,
doi = "10.1073/pnas.1809969115",
language = "English",
volume = "115",
pages = "11567--11572",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "45",
}