TY - JOUR TI - The PNKD gene is associated with tourette disorder and tic disorder in a multiplex family DO - https://doi.org/doi:10.7282/T3251MNS PY - 2017 AB - Tourette 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. KW - Microbiology and Molecular Genetics KW - Tourette syndrome KW - Movement disorders--Genetic aspects LA - eng ER -