Parkinson’s disease (PD) represents the most common neurodegenerative movement disorder. We recently identified 16 novel genes associated with PD. In this study, we focused the attention on the common and rare variants identified in the lysosomal K⁺ channel TMEM175. The study includes a detailed clinical and genetic analysis of 400 cases and 300 controls. Molecular studies were performed on patient-derived fibroblasts. The functional properties of the mutant channels were assessed by patch-clamp technique and co-immunoprecipitation. We have found that TMEM175 was highly expressed in dopaminergic neurons of the substantia nigra pars compacta and in microglia of the cerebral cortex of the human brain. Four common variants were associated with PD, including two novel variants rs2290402 (c.-10C > T) and rs80114247 (c.T1022C, p.M341T), located in the Kozak consensus sequence and TM3II domain, respectively. We also disclosed 13 novel highly penetrant detrimental mutations in the TMEM175 gene associated with PD. At least nine of these mutations (p.R35C, p. R183X, p.A270T, p.P308L, p.S348L, p. L405V, p.R414W, p.P427fs, p.R481W) may be sufficient to cause the disease, and the presence of mutations of other genes correlated with an earlier disease onset. In vitro functional analysis of the ion channel encoded by the mutated TMEM175 gene revealed a loss of the K⁺ conductance and a reduced channel affinity for Akt. Moreover, we observed an impaired autophagic/lysosomal proteolytic flux and an increase expression of unfolded protein response markers in patient-derived fibroblasts. These data suggest that mutations in TMEM175 gene may contribute to the pathophysiology of PD.

帕金森病 (PD) 是最常见的神经退行性运动障碍。我们最近发现了 16 个与 PD 相关的新基因。在这项研究中，我们将注意力集中在溶酶体 K ⁺通道 TMEM175 中发现的常见和罕见变异上。该研究包括对 400 个病例和 300 个对照的详细临床和遗传分析。对患者来源的成纤维细胞进行了分子研究。通过膜片钳技术和免疫共沉淀评估突变通道的功能特性。我们发现TMEM175在黑质致密部的多巴胺能神经元和人脑大脑皮层的小胶质细胞中高度表达。四种常见变异与 PD 相关，包括两种新变异 rs2290402 (c.-10C > T) 和 rs80114247 (c.T1022C, p.M341T)，分别位于 Kozak 共有序列和 TM3II 结构域。我们还披露了与 PD 相关的TMEM175基因中的 13 种新型高度外显性有害突变。这些突变中至少有九个（p.R35C、p.R183X、p.A270T、p.P308L、p.S348L、p.L405V、p.R414W、p.P427fs、p.R481W）可能足以引起疾病，以及其他基因突变的存在与早期疾病发作相关。突变TMEM175编码的离子通道的体外功能分析^{基因揭示了 K +}电导的损失和对 Akt 的通道亲和力降低。此外，我们观察到自噬/溶酶体蛋白水解通量受损以及患者来源的成纤维细胞中未折叠蛋白反应标记物的表达增加。这些数据表明TMEM175基因突变可能有助于 PD 的病理生理学。