Coding mutations in NUS1 contribute to Parkinson’s disease
- 22 October 2018
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 115 (45), 11567-11572
- https://doi.org/10.1073/pnas.1809969115
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.Funding Information
- national key plan for scientific research and development of China (2016YFC1306000)
- National Natural Science Foundation of China (81430023)
This publication has 33 references indexed in Scilit:
- Progress in unraveling the genetic etiology of Parkinson disease in a genomic eraTrends in Genetics, 2015
- Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's diseaseNature Genetics, 2014
- Parkinsonism syndrome in heterozygotes for Niemann–Pick C1Journal of the Neurological Sciences, 2013
- Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum DisordersScience, 2012
- De novo mutations revealed by whole-exome sequencing are strongly associated with autismNature, 2012
- Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutationsNature Genetics, 2011
- Cholesterol involvement in the pathogenesis of neurodegenerative diseasesMolecular and Cellular Neuroscience, 2010
- Rate, molecular spectrum, and consequences of human mutationProceedings of the National Academy of Sciences of the United States of America, 2010
- A Swedish family with de novo α-synuclein A53T mutation: Evidence for early cortical dysfunctionParkinsonism & Related Disorders, 2009
- Brain neutral lipids mass is increased in α‐synuclein gene‐ablated miceJournal of Neurochemistry, 2007