Abstract
Aim: To conduct the clinical, genetic, and molecular characterization of 494 Han Chinese subjects with tic disorders (TD).Methods: In the present study, we performed the mutational analysis of 22 mitochondrial tRNA genes in a large cohort of 494 Han Chinese subjects with TD via Sanger sequencing. These variants were then assessed for their pathogenic potential via phylogenetic, functional, and structural analyses.Results: A total of 73 tRNA gene variants (49 known and 24 novel) on 22 tRNA genes were identified. Among these, 18 tRNA variants that were absent or present in <1% of 485 Chinese control patient samples were localized to highly conserved nucleotides, or changed the modified nucleotides, and had the potential structural to alter tRNA structure and function. These variants were thus considered to be TD-associated mutations. In total, 25 subjects carried one of these 18 putative TD-associated tRNA variants with the total prevalence of 4.96%.Limitations: The phenotypic variability and incomplete penetrance of tic disorders in pedigrees carrying these tRNA mutations suggested the involvement of modifier factors, such as nuclear encoded genes associated mitochondrion, mitochondrial haplotypes, epigenetic, and environmental factors.Conclusion: Our data provide the evidence that mitochondrial tRNA mutations are the important causes of tic disorders among Chinese population. These findings also advance current understanding regarding the clinical relevance of tRNA mutations, and will guide future studies aimed at elucidating the pathophysiology of maternal tic disorders.
Highlights
Tic disorders (TD) are a form of neuropsychiatric condition wherein individuals suffer from repetitive involuntary motor or vocal tics [1,2]
Most efforts to identify genetic mutations associated with TD risk have centered on nuclear genes which mutations in IMMP2L, CNTNAP2, SLITRK1, NLGN4X, and MRPL3 have been linked to TD risk [6,7,8,9,10]
Participants suffered a range of classical TD symptoms, including 415 participants that experienced involuntary blinking, 246 that were affected by involuntary grimacing, 234 that suffered involuntary throat clearing/phonation, 131 that involuntarily shrugged their shoulders, 140 that suffered from involuntary head shaking, and 26 that exhibited involuntary spitting
Summary
Tic disorders (TD) are a form of neuropsychiatric condition wherein individuals suffer from repetitive involuntary motor or vocal tics [1,2]. TD are thought to develop through the interactions between both genetic and environmental variables. Such tics affect up to 25% of children, individuals of any age can be affected [3,4]. The DSM-V includes three different TDs, including Tourette’s Syndrome (TS), chronic tic disorder (CTD), and provisional tic disorder (PTD) [5]. Most efforts to identify genetic mutations associated with TD risk have centered on nuclear genes which mutations in IMMP2L, CNTNAP2, SLITRK1, NLGN4X, and MRPL3 have been linked to TD risk [6,7,8,9,10]. IMMP2L codes for inner membrane peptidase subunit 2, which is a protease that is present in mitochondria and cleaves sorting
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