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Coding mutations in NUS1 contribute to Parkinson's disease.

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... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America November 6, 2018, Vol.115(45), pp.11567-11572
Main Author: Guo, Ji-Feng
Other Authors: Zhang, Lu , Li, Kai , Mei, Jun-Pu , Xue, Jin , Chen, Jia , Tang, Xia , Shen, Lu , Jiang, Hong , Chen, Chao , Guo, Hui , Wu, Xue-Li , Sun, Si-Long , Xu, Qian , Sun, Qi-Ying , Chan, Piu , Shang, Hui-Fang , Wang, Tao , Zhao, Guo-Hua , Liu
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1809969115
Link: http://search.proquest.com/docview/2130800383/?pq-origsite=primo
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title: Coding mutations in NUS1 contribute to Parkinson's disease.
format: Article
creator:
  • Guo, Ji-Feng
  • Zhang, Lu
  • Li, Kai
  • Mei, Jun-Pu
  • Xue, Jin
  • Chen, Jia
  • Tang, Xia
  • Shen, Lu
  • Jiang, Hong
  • Chen, Chao
  • Guo, Hui
  • Wu, Xue-Li
  • Sun, Si-Long
  • Xu, Qian
  • Sun, Qi-Ying
  • Chan, Piu
  • Shang, Hui-Fang
  • Wang, Tao
  • Zhao, Guo-Hua
  • Liu
subjects:
  • Adult–Genetics
  • Age of Onset–Antagonists & Inhibitors
  • Animals–Genetics
  • Apoptosis–Metabolism
  • Aryl Hydrocarbon Receptor Nuclear Translocator–Metabolism
  • Base Sequence–Pathology
  • Brain–Metabolism
  • Case-Control Studies–Metabolism
  • Cohort Studies–Pathology
  • Disease Models, Animal–Antagonists & Inhibitors
  • Dopamine–Genetics
  • Dopaminergic Neurons–Metabolism
  • Drosophila Proteins–Genetics
  • Drosophila Melanogaster–Metabolism
  • Early Diagnosis–Genetics
  • Female–Metabolism
  • Gene Expression–Diagnosis
  • Gene Regulatory Networks
ispartof: Proceedings of the National Academy of Sciences of the United States of America, November 6, 2018, Vol.115(45), pp.11567-11572
description: 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. Parkinson's disease | exome sequencing | de novo mutations | disease-risk gene | neurodegenerative disorders
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1809969115
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleCoding mutations in NUS1 contribute to Parkinson's disease.
creatorGuo, Ji-Feng ; Zhang, Lu ; Li, Kai ; Mei, Jun-Pu ; Xue, Jin ; Chen, Jia ; Tang, Xia ; Shen, Lu ; Jiang, Hong ; Chen, Chao ; Guo, Hui ; Wu, Xue-Li ; Sun, Si-Long ; Xu, Qian ; Sun, Qi-Ying ; Chan, Piu ; Shang, Hui-Fang ; Wang, Tao ; Zhao, Guo-Hua ; Liu
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ispartofProceedings of the National Academy of Sciences of the United States of America, November 6, 2018, Vol.115(45), pp.11567-11572
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1809969115
subjectAdult–Genetics ; Age of Onset–Antagonists & Inhibitors ; Animals–Genetics ; Apoptosis–Metabolism ; Aryl Hydrocarbon Receptor Nuclear Translocator–Metabolism ; Base Sequence–Pathology ; Brain–Metabolism ; Case-Control Studies–Metabolism ; Cohort Studies–Pathology ; Disease Models, Animal–Antagonists & Inhibitors ; Dopamine–Genetics ; Dopaminergic Neurons–Metabolism ; Drosophila Proteins–Genetics ; Drosophila Melanogaster–Metabolism ; Early Diagnosis–Genetics ; Female–Metabolism ; Gene Expression–Diagnosis ; Gene Regulatory Networks
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descriptionWhole-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. Parkinson's disease | exome sequencing | de novo mutations | disease-risk gene | neurodegenerative disorders
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titleCoding mutations in NUS1 contribute to Parkinson's disease.
authorGuo, Ji-Feng ; Zhang, Lu ; Li, Kai ; Mei, Jun-Pu ; Xue, Jin ; Chen, Jia ; Tang, Xia ; Shen, Lu ; Jiang, Hong ; Chen, Chao ; Guo, Hui ; Wu, Xue-Li ; Sun, Si-Long ; Xu, Qian ; Sun, Qi-Ying ; Chan, Piu ; Shang, Hui-Fang ; Wang, Tao ; Zhao, Guo-Hua ; Liu
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