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The PNKD gene is associated with tourette disorder and tic disorder in a multiplex family
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Sun, Nawei. The PNKD gene is associated with tourette disorder and tic disorder in a multiplex family. Retrieved from https://doi.org/doi:10.7282/T3251MNS

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TitleThe PNKD gene is associated with tourette disorder and tic disorder in a multiplex family
NameSun, Nawei (author); Firestein, Bonnie L. (chair); Brzustowicz, Linda (internal member); Tischfield, Jay A. (internal member); Heiman, Gary (internal member); Hart, Ronald (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2017
Other Date2017-01 (degree)
SubjectMicrobiology and Molecular Genetics, Tourette syndrome, Movement disorders--Genetic aspects
Extent1 online resource (xi, 93 p. : ill.)
DescriptionTourette Disorder (TD) is a highly heritable neuropsychiatric and neurodevelopmental disorder characterized by the presence of both motor and vocal tics. Disruptions of particular genes have been identified in subsets of TD patients. However, none of the findings have been replicated, probably due to the complex and heterogeneous genetic architecture of TD that involves both common and rare variants. To understand the etiology of TD, functional analyses are required to characterize the molecular and cellular consequences caused by mutations in candidate genes. Such molecular and cellular alterations may converge into common biological pathways underlying the heterogeneous genetic etiology of TD patients. In CHAPTER 1, we review specific genes implicated in TD etiology, discuss the functions of these genes in the mammalian central nervous system and the corresponding behavioral anomalies exhibited in animal models, and importantly, review functional analyses that can be performed to evaluate the role(s) that the genetic disruptions might play in TD. Specifically, the functional assays include novel cell culture systems, genome editing techniques, bioinformatics approaches, transcriptomic analyses, and genetically modified animal models applied or developed to study genes associated with TD or with other neurodevelopmental and neuropsychiatric disorders. In CHAPTER 2, we reported that a rare heterozygous nonsense mutation at the PNKD gene co-segregating with individuals affected by TD or Tic disorders in a multiplex family was identified by whole exome sequencing. 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. We found that transcript and protein levels of the PNKD long isoform were reduced in neurons derived from the individuals with TD probably due to nonsense-mediated mRNA decay. Additionally, we demonstrated that the PNKD long protein monomer oligomerizes with itself as well as interacts the synaptic active zone protein RIMS1α. Therefore, we concluded that the reduction of the PNKD long protein in the neurons of TD patients in this multiplex family may contribute to TD.
NotePh.D.
NoteIncludes bibliographical references
Noteby Nawei Sun
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3251MNS
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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