Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, 610041, China.
Mol Neurobiol. 2021 Apr;58(4):1583-1592. doi: 10.1007/s12035-020-02218-4. Epub 2020 Nov 20.
Recent genetic studies clearly indicate that variants in several lysosomal genes act as risk factors for idiopathic Parkinson's disease (PD). Variants in the co-activator of glucocerebrosidase gene (GBA) and the four active saposins (Sap A-D) which are encoded by the prosaposin gene (PSAP) are of particular interest; however, their genetic roles in PD are unknown. Whole-exome sequencing and Sanger sequencing were used to assess the genetic etiology of 400 autosomal dominant inherited PD (ADPD) and 300 sporadic PD (SPD) patients. Variants from public databases, including Genome Aggregation Database-East Asian (GnomAD_EAS) and Chinese Millionome Database (CMDB), were used as control groups. Burden analysis based on gene and domains level were performed to investigate the role of rare PSAP variants in PD. Six rare and likely pathogenic variants, located in the Sap A-D domains, were identified and accounted for 0.75% (3/400) of ADPD and 1.33% (4/300) of SPD in the Chinese population. Based on the gene or domain, burden analysis showed that damaging missense variants in SapC had statistical significance on the risk of developing PD. Interestingly, rs4747203, an intronic variant potentially linked to PSAP expression, was associated with reduced risk for PD (p = 8.6e-7 in GnomAD EAS and p = 0.002 in Chinese). Clinically, patients carrying the likely pathogenic variants presented typical PD motor symptoms and responded well to levodopa treatment. Six out of seven patients carrying the likely pathogenic variants of PSAP presented slow disease progression, and none of the patients developed cognitive impairment. Our study expands the spectrum of mutations associated with the risk of developing PD and enhances the understanding of the relationship of the clinical phenotype of PD with PSAP variants.
最近的遗传研究清楚地表明，几种溶酶体基因的变异可作为特发性帕金森病（PD）的风险因素。葡糖脑苷脂酶基因（GBA）和前脑啡肽原基因（PSAP）编码的四个活性脑苷脂激活蛋白（Sap A-D）的共激活因子的变异特别引人注目；然而，它们在 PD 中的遗传作用尚不清楚。全外显子组测序和 Sanger 测序用于评估 400 例常染色体显性遗传 PD（ADPD）和 300 例散发性 PD（SPD）患者的遗传病因。来自公共数据库的变异，包括基因组聚集数据库-东亚（GnomAD_EAS）和中国百万基因组数据库（CMDB），被用作对照组。基于基因和结构域水平进行的负担分析，以研究罕见 PSAP 变异在 PD 中的作用。鉴定出 6 个位于 Sap A-D 结构域的罕见且可能致病性变异，占中国人群 ADPD 的 0.75%（3/400）和 SPD 的 1.33%（4/300）。基于基因或结构域，负担分析表明 SapC 中的破坏性错义变异与 PD 发病风险具有统计学意义。有趣的是，rs4747203，一个潜在与 PSAP 表达相关的内含子变异，与 PD 风险降低相关（GnomAD EAS 中的 p = 8.6e-7，中国的 p = 0.002）。临床上，携带可能致病性变异的患者表现出典型的 PD 运动症状，对左旋多巴治疗反应良好。携带 PSAP 可能致病性变异的 7 名患者中有 6 名患者疾病进展缓慢，且无一例患者出现认知障碍。我们的研究扩展了与 PD 发病风险相关的突变谱，并增强了对 PD 临床表型与 PSAP 变异关系的理解。
