BackgroundMore than 60% of paroxysmal kinesigenic dyskinesia (PKD) cases are of uncertain variants.ObjectiveThe aim was to elucidate novel genetic contribution to PKD.MethodsA total of 476 probands with uncertain genetic causes were enrolled for whole‐exome sequencing. A method of case–control analysis was applied to identify the candidate genes. Whole‐cell patch‐clamp recording was applied to verify the electrophysiological impact of the identified variants. A mouse model with cerebellar heterozygous knockout of the candidate gene was developed via adeno‐associated virus injection, and dystonia‐like phenotype inducement and rotarod tests were performed. In vivo multiunit electrical recording was applied to investigate the change in neural excitability in knockout mice.ResultsHeterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) clustered in PKD patients were compared with those in the control groups. Fifteen variants were detected in 16 of 522 probands (frequency = 3.07%). Patients with KCNJ10 variants tended to have a milder manifestation compared to those with PRRT2 (proline‐rich transmembrane protein 2) variants. KCNJ10 variants partially altered the transmembrane location of inwardly rectifying potassium channel 4.1 (Kir4.1). The Kcnj10 expression is consistent with the natural course of PKD. Variants resulted in different degrees of reduction in cell Kir4.1 currents, and mice with heterozygous conditional knockout of Kcnj10 in the cerebellum presented dystonic posture, together with poor motor coordination and motor learning ability in rotarod tests. The firing rate of deep cerebellar nuclei was significantly elevated in Kcnj10‐cKO mice.ConclusionWe identified heterozygous variants of KCNJ10 in PKD. Impaired function of Kir4.1 might lead to abnormal neuronal excitability, which attributed to PKD. © 2024 International Parkinson and Movement Disorder Society.

中文翻译：

---

影响 Kir4.1 通道的杂合 KCNJ10 变体导致阵发性运动动力学障碍


背景超过 60% 的阵发性运动动力学障碍 （PKD） 病例具有不确定的变异。目的阐明对 PKD 的新遗传贡献。方法共招募 476 例遗传原因不明的先证者进行全外显子组测序。采用病例对照分析方法鉴定候选基因。应用全细胞膜片钳记录以验证已鉴定变异的电生理影响。通过腺相关病毒注射开发候选基因小脑杂合敲除小鼠模型，并进行肌张力障碍样表型诱导和旋转试验。体内多单位电记录用于研究敲除小鼠神经兴奋性的变化。结果将 PKD 患者聚集的钾向内整流通道亚家族 J 成员 10 （KCNJ10） 的杂合变异与对照组进行比较。在 522 例先证者中的 16 例中检测到 15 个变异 （频率 = 3.07%）。与 PRRT2 （富含脯氨酸的跨膜蛋白 2） 变体患者相比，KCNJ10 变体的患者往往表现较轻。KCNJ10 变体部分改变了向内整流钾通道 4.1 （Kir4.1） 的跨膜位置。Kcnj10 表达与 PKD 的自然病程一致。变异导致细胞 Kir4.1 电流不同程度的降低，小脑中 Kcnj10 杂合条件敲除的小鼠在旋转试验中表现出肌张力障碍姿势，以及运动协调和运动学习能力差。Kcnj10-cKO 小鼠小脑深核的放电率显着升高。结论我们在 PKD 中鉴定了 KCNJ10 的杂合变异。Kir4 功能受损。1 可能导致异常的神经元兴奋性，这归因于 PKD。© 2024 年国际帕金森和运动障碍协会。