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The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family

Tourette Disorder (TD) is a childhood-onset neuropsychiatric and neurodevelopmental disorder characterized by the presence of both motor and vocal tics. The genetic architecture of TD is believed to be complex and heterogeneous. Nevertheless, DNA sequence variants co-segregating with TD phenotypes w...

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Autores principales: Sun, Nawei, Nasello, Cara, Deng, Li, Wang, Nan, Zhang, Yeting, Xu, Zihui, Song, Zhichao, Kwan, Kelvin, King, Robert A., Pang, Zhiping P., Xing, Jinchuan, Heiman, Gary A., Tischfield, Jay A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847395/
https://www.ncbi.nlm.nih.gov/pubmed/28894297
http://dx.doi.org/10.1038/mp.2017.179
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author Sun, Nawei
Nasello, Cara
Deng, Li
Wang, Nan
Zhang, Yeting
Xu, Zihui
Song, Zhichao
Kwan, Kelvin
King, Robert A.
Pang, Zhiping P.
Xing, Jinchuan
Heiman, Gary A.
Tischfield, Jay A.
author_facet Sun, Nawei
Nasello, Cara
Deng, Li
Wang, Nan
Zhang, Yeting
Xu, Zihui
Song, Zhichao
Kwan, Kelvin
King, Robert A.
Pang, Zhiping P.
Xing, Jinchuan
Heiman, Gary A.
Tischfield, Jay A.
author_sort Sun, Nawei
collection PubMed
description Tourette Disorder (TD) is a childhood-onset neuropsychiatric and neurodevelopmental disorder characterized by the presence of both motor and vocal tics. The genetic architecture of TD is believed to be complex and heterogeneous. Nevertheless, DNA sequence variants co-segregating with TD phenotypes within multiplex families have been identified. This report examines whole exomes of affected and unaffected individuals in a multiplex TD family to discover genes involved in the TD etiology. We performed whole exome sequencing on six out of nine members in a three-generation TD multiplex family. Putative deleterious sequence variants co-segregating with TD patients were identified by our in-house bioinformatics pipeline. Induced pluripotent stem cells (iPSCs) were generated from one unaffected and two TD affected individuals. Neurons were derived from the iPSCs and biochemical assays were conducted to evaluate possible molecular differences between affected and unaffected. A rare heterozygous nonsense mutation in PNKD was co-segregated with TD in this multiplex family. Transcript and protein levels of the PNKD long isoform were reduced in neurons derived from the individuals with TD due to the nonsense mutation, indicating nonsense-mediated mRNA decay. We demonstrated that the PNKD long isoform monomer oligomerizes with itself as well as interacts with the synaptic active zone protein RIMS1α. We concluded that reduced PNKD long isoform levels are detected in all affected individuals and we provide evidence for a mechanism where by this might contribute to the TD phenotype.
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spelling pubmed-58473952018-03-14 The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family Sun, Nawei Nasello, Cara Deng, Li Wang, Nan Zhang, Yeting Xu, Zihui Song, Zhichao Kwan, Kelvin King, Robert A. Pang, Zhiping P. Xing, Jinchuan Heiman, Gary A. Tischfield, Jay A. Mol Psychiatry Article Tourette Disorder (TD) is a childhood-onset neuropsychiatric and neurodevelopmental disorder characterized by the presence of both motor and vocal tics. The genetic architecture of TD is believed to be complex and heterogeneous. Nevertheless, DNA sequence variants co-segregating with TD phenotypes within multiplex families have been identified. This report examines whole exomes of affected and unaffected individuals in a multiplex TD family to discover genes involved in the TD etiology. We performed whole exome sequencing on six out of nine members in a three-generation TD multiplex family. Putative deleterious sequence variants co-segregating with TD patients were identified by our in-house bioinformatics pipeline. Induced pluripotent stem cells (iPSCs) were generated from one unaffected and two TD affected individuals. Neurons were derived from the iPSCs and biochemical assays were conducted to evaluate possible molecular differences between affected and unaffected. A rare heterozygous nonsense mutation in PNKD was co-segregated with TD in this multiplex family. Transcript and protein levels of the PNKD long isoform were reduced in neurons derived from the individuals with TD due to the nonsense mutation, indicating nonsense-mediated mRNA decay. We demonstrated that the PNKD long isoform monomer oligomerizes with itself as well as interacts with the synaptic active zone protein RIMS1α. We concluded that reduced PNKD long isoform levels are detected in all affected individuals and we provide evidence for a mechanism where by this might contribute to the TD phenotype. 2017-09-12 2018-06 /pmc/articles/PMC5847395/ /pubmed/28894297 http://dx.doi.org/10.1038/mp.2017.179 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Sun, Nawei
Nasello, Cara
Deng, Li
Wang, Nan
Zhang, Yeting
Xu, Zihui
Song, Zhichao
Kwan, Kelvin
King, Robert A.
Pang, Zhiping P.
Xing, Jinchuan
Heiman, Gary A.
Tischfield, Jay A.
The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family
title The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family
title_full The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family
title_fullStr The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family
title_full_unstemmed The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family
title_short The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family
title_sort pnkd gene is associated with tourette disorder or tic disorder in a multiplex family
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847395/
https://www.ncbi.nlm.nih.gov/pubmed/28894297
http://dx.doi.org/10.1038/mp.2017.179
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