The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family.
The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family.
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DOI：
10.1038/mp.2017.179
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发表时间：
2018-06
影响因子：
11
通讯作者：
Tischfield JA
中科院分区：
文献类型：
--
作者：
Sun N;Nasello C;Deng L;Wang N;Zhang Y;Xu Z;Song Z;Kwan K;King RA;Pang ZP;Xing J;Heiman GA;Tischfield JA
抽动秽语症（TD）是一种儿童期发病的神经精神和神经发育障碍，其特征是存在运动和声音抽搐。TD的遗传结构被认为是复杂和异质的。然而，在多个家族中已经发现了与TD表型共分离的DNA序列变异。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，以发现与TD病因有关的基因。我们对三代TD多重家族的9个成员中的6个进行了全外显子组测序。与TD患者共分离的推定有害序列变异是由我们内部的生物信息学管道确定的。诱导多能干细胞（iPSCs）由一名未受影响的个体和两名TD患者产生。神经元来源于iPSCs，并进行生化分析以评估受影响和未受影响之间可能的分子差异。在这个多重家族中，一个罕见的PNKD杂合无义突变与TD共分离。由于无义突变，来自TD个体的神经元中PNKD长异构体的转录物和蛋白质水平降低，表明无义介导的mRNA衰变。我们证明了PNKD长异构体单体与自身寡聚，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都检测到PNKD长同种异构体水平的降低，我们为这可能导致TD表型的机制提供了证据。
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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影响因子：
46.9
作者：
Hu, Hao;Roach, Jared C.;Coon, Hilary;Guthery, Stephen L.;Voelkerding, Karl V.;Margraf, Rebecca L.;Durtschi, Jacob D.;Tavtigian, Sean V.;Shankaracharya;Wu, Wilfred;Scheet, Paul;Wang, Shuoguo;Xing, Jinchuan;Glusman, Gustavo;Hubley, Robert;Li, Hong;Garg, Vidu;Moore, Barry;Hood, Leroy;Galas, David J.;Srivastava, Deepak;Reese, Martin G.;Jorde, Lynn B.;Yandell, Mark;Huff, Chad D.
通讯作者：
Huff, Chad D.
影响因子：
3.5
作者：
Ghezzi, Daniele;Viscomi, Carlo;Zeviani, Massimo
通讯作者：
Zeviani, Massimo
影响因子：
9.9
作者：
Gilbert, D. L.;Christian, B. T.;Sallee, F. R.
通讯作者：
Sallee, F. R.
影响因子：
5.3
作者：
Israelashvili, Michal;Bar-Gad, Izhar
通讯作者：
Bar-Gad, Izhar
DOI：
10.1002/cne.22206
发表时间：
2010-02-01
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Kataoka Y;Kalanithi PS;Grantz H;Schwartz ML;Saper C;Leckman JF;Vaccarino FM
通讯作者：
Vaccarino FM