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 whereby this might contribute to the TD phenotype.

中文翻译：

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PNKD基因与多重家族中的Tourette病或Tic病有关。

Tourette障碍（TD）是儿童期发作的神经精神病和神经发育障碍，其特征是运动和发声抽动同时存在。TD的遗传结构被认为是复杂且异质的。然而，已经鉴定了在多重家族中与TD表型共分离的DNA序列变体。本报告检查了多重TD家族中受影响和未受影响个体的整个外显子组，以发现涉及TD病因的基因。我们对三代TD多重序列家族的9个成员中的6个进行了全外显子组测序。通过我们内部的生物信息学渠道，可以确定与TD患者共分离的有害序列变异体。诱导多能干细胞（iPSC）从一个未受影响的人和两个受TD感染的个体中产生。神经元从iPSC衍生而来，并进行了生化分析以评估受影响和未受影响之间可能存在的分子差异。在这个多重家族中，PNKD中罕见的杂合性无意义突变与TD共分离。由于无义突变，来自患有TD的个体的神经元中PNKD长同工型的转录物和蛋白质水平降低，表明无义介导的mRNA衰减。我们证明，PNKD长同工型单体自身低聚，并与突触活性区蛋白RIMS1α相互作用。我们得出的结论是，在所有受影响的个体中均检测到降低的PNKD长异构体水平，并且我们提供了可能有助于TD表型的机制的证据。