Gao Lili, Lin Min, Wu Chenghan, Liao Yuansheng, Lin Zuopeng, Yan Xiaohua, Lin Sheng, Wang Yinzhou, Chen Jing, Zheng Zhaocong, Lin Jushan, Zhang Sheng, Guan Jianhua, Qiu Yan, Liao Jilian, Wu Lihua
Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Wuhan Kindstar Clinical Diagnostic Co., Kindstar Globalgene Technology, Inc, Wuhan, China.
Eur J Neurol. 2025 Feb;32(2):e70086. doi: 10.1111/ene.70086.
Autosomal dominant polycystic kidney disease (ADPKD) is frequently complicated by intracranial aneurysms (IAs). However, the genetic factors driving the elevated IA risk in ADPKD remain poorly understood. In this study, we identified a novel PKD1 mutation associated with a remarkably high IA incidence in a large Chinese ADPKD family.
We conducted whole-exome sequencing in a three-generation Chinese ADPKD family (n = 24) characterized by an unusually high IA prevalence. The pathogenicity of the identified PKD1 variant was validated through comprehensive functional studies, including protein localization, calcium signaling, and endothelial cell behavior analyses.
We discovered a novel PKD1 mutation (c.G10086T) that co-segregated with disease in all affected family members. Notably, 38.1% (8/21) of the mutation carriers developed IAs, a significantly higher rate than reported in general ADPKD populations (4%-11.5%). Functional studies revealed that this mutation disrupted polycystin-1 trafficking and impaired calcium signaling, leading to endothelial dysfunction. In vitro experiments demonstrated enhanced angiogenic potential and compromised vascular integrity in cells expressing mutant PKD1.
The newly identified PKD1:c.G10086T mutation represents a high-risk genetic variant for IA development in ADPKD. Our findings provide new insights into the vascular complications of ADPKD and suggest that PKD1 genotyping may help identify patients requiring intensive IA surveillance. This study supports the development of mutation-specific screening strategies for ADPKD-associated vascular complications.
常染色体显性多囊肾病（ADPKD）常并发颅内动脉瘤（IA）。然而，导致ADPKD患者IA风险升高的遗传因素仍知之甚少。在本研究中，我们在一个大型中国ADPKD家系中鉴定出一种与极高IA发病率相关的新型PKD1突变。
我们对一个三代中国ADPKD家系（n = 24）进行了全外显子组测序，该家系的IA患病率异常高。通过全面的功能研究，包括蛋白质定位、钙信号传导和内皮细胞行为分析，验证了所鉴定的PKD1变体的致病性。
我们发现了一种新型PKD1突变（c.G10086T），该突变在所有受影响的家庭成员中与疾病共分离。值得注意的是，38.1%（8/21）的突变携带者发生了IA，这一比例显著高于一般ADPKD人群（4%-11.5%）的报道。功能研究表明，该突变破坏了多囊蛋白-1的运输并损害了钙信号传导，导致内皮功能障碍。体外实验表明，表达突变型PKD1的细胞具有增强的血管生成潜力和受损的血管完整性。
新鉴定的PKD1:c.G10086T突变是ADPKD患者发生IA的高风险遗传变异。我们的研究结果为ADPKD的血管并发症提供了新的见解，并表明PKD1基因分型可能有助于识别需要加强IA监测的患者。本研究支持开发针对ADPKD相关血管并发症的突变特异性筛查策略。
