Coding mutations in NUS1 contribute to Parkinson's disease

Ji Feng Guo, Lu Zhang, Kai Li, Jun Pu Mei, Jin Xue, Jia Chen, Xia Tang, Lu Shen, Hong Jiang, Chao Chen, Hui Guo, Xue Li Wu, Si Long Sun, Qian Xu, Qi Ying Sun, Piu Chan, Hui Fang Shang, Tao Wang, Guo Hua Zhao, Jing Yu LiuXue Feng Xie, Yi Qi Jiang, Zhen Hua Liu, Yu Wen Zhao, Zuo Bin Zhu, Jia Da Li, Zheng Mao Hu, Xin Xiang Yan, Xiao Dong Fang, Guang Hui Wang, Feng Yu Zhang, Kun Xia, Chun Yu Liu, Xiong Wei Zhu, Zhen Yu Yue, Shuai Cheng Li, Huai Bin Cai, Zhuo Hua Zhang, Ran Hui Duan, Bei Sha Tang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11567-11572
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number45
DOIs
Publication statusPublished - Oct 2018

Scopus Subject Areas

  • General

User-Defined Keywords

  • De novo mutations
  • Disease-risk gene
  • Exome sequencing
  • Neurodegenerative disorders
  • Parkinson's disease

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