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

Nawei Sun; Cara Nasello; Li Deng; Nan Wang; Yeting Zhang; Zihui Xu; Zhichao Song; Kelvin Kwan; Robert A. King; Zhiping Pang; Jinchuan Xing; Gary A. Heiman; Jay A. Tischfield

doi:10.1038/mp.2017.179

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

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

Nawei Sun, Cara Nasello, Li Deng, Nan Wang, Yeting Zhang, Zihui Xu, Zhichao Song, Kelvin Kwan, Robert A. King, Zhiping Pang, …

Molecular psychiatry, Vol.23(6), pp.1487-1495

09/12/2017

DOI: https://doi.org/10.1038/mp.2017.179

PMCID: PMC5847395

PMID: 28894297

Abstract

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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Title: Subtitle: The PNKD gene is associated with Tourette disorder or Tic disorder in a multiplex family
Creators: Nawei Sun - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Cara Nasello - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Li Deng - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Nan Wang - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Yeting Zhang - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Zihui Xu - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Zhichao Song - Rutgers, The State University of New Jersey
Kelvin Kwan
Robert A. King - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Zhiping Pang - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Jinchuan Xing - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Gary A. Heiman - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Jay A. Tischfield - Department of Genetics, Rutgers University, Piscataway, NJ, USA Human Genetics Institute of New Jersey, Piscataway, NJ, USA Department of Cell Biology and Neuroscience, Piscataway, NJ, USA Child Study Center, Yale School of Medicine, New Haven, CT, USA Child Health Institute of New Jersey, New Brunswick, NJ, USA
Publication Details: Molecular psychiatry, Vol.23(6), pp.1487-1495
Date published: 09/12/2017
Academic Unit: W.M. Keck Center of Collaborative Neuroscience
Language: English
Resource Type: Journal article
Identifiers: 991031726478104646