Journal Article

Coding mutations in NUS1 contribute to Parkinson’s disease

Li, Kai, Zhao, Yu-wen, Hu, Zheng-mao, Tang, Xia, Chan, Piu, Sun, Si-long, Zhu, Xiong-wei, Yan, Xin-xiang, Wang, Tao, Li, Jia-da, Zhao, Guo-hua, Tang, Bei-sha, Zhang, Lu, Sun, Qi-ying, Zhu, Zuo-bin, Chen, Chao, Xie, Xue-feng, Xia, Kun, Jiang, Yi-qi, Duan, Ran-hui, Guo, Ji-feng, Liu, Chun-yu, Yue, Zhen-yu, Li, Shuai Cheng, Xue, Jin, Cai, Huai-bin, Chen, Jia, Jiang, Hong, Xu, Qian, Mei, Jun-pu, Liu, Zhen-hua, Wang, Guang-hui, Shang, Hui-fang, Guo, Hui, Wu, Xue-li, Fang, Xiao-dong, Zhang, Feng-yu, Zhang, Zhuo-hua, Shen, Lu, Liu, Jing-yu

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Adult / Age of Onset / Animals / Apoptosis / Apoptosis - genetics / Aryl Hydrocarbon Receptor Nuclear Translocator - antagonists & inhibitors / Aryl Hydrocarbon Receptor Nuclear Translocator - genetics / Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism / Base Sequence / Biological Sciences / Brain / Brain - metabolism / Brain - pathology / Case-Control Studies / Cohort Studies / Disease Models, Animal / Dopamine / Dopamine - metabolism / Dopamine receptors / Dopaminergic Neurons - metabolism / Dopaminergic Neurons - pathology / Drosophila melanogaster - genetics / Drosophila melanogaster - metabolism / Drosophila Proteins - antagonists & inhibitors / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / Early Diagnosis / Female / Fruit flies / Gene Expression / Gene Regulatory Networks / Gene sequencing / Genetic factors / Genetics / Humans / Male / Movement disorders / Mutation / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neural coding / Neurodegenerative diseases / Parents / Parkinson Disease - diagnosis / Parkinson Disease - genetics / Parkinson Disease - metabolism / Parkinson Disease - pathology / Parkinson's disease / Pathogenesis / Patients / Receptors, Cell Surface - genetics / Receptors, Cell Surface - metabolism / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Siblings