Table 1_An intronic micro-deletion impacts the transcription and translation of PKD1 gene.docx

Polycystin-1 (PC1), encoded by the PKD1 gene, forms a complex with polycystin-2 (PKD2; 173910) that regulates multiple signaling pathways to maintain normal renal tubular structure and function. Mutations in the PKD1 gene are the primary cause of type 1 PKD (polycystic kidney disease), accounting for 78%–85% of all PKD cases. In this study, we report a case of a boy presenting with microscopic hematuria with multiple renal cysts and carrying an unreported intronic variant, c.12445-34_12445-10del, in the PKD1 gene inherited from his father who also presented PKD. Sanger sequencing and reverse transcription polymerase chain reaction (RT-PCR) for minigene splicing assays showed two abnormal splicing alterations with the c.12445-34_12445-10del variant at the mRNA level: one causes a 16-bp deletion in exon 46, resulting in premature protein termination (p.Phe4149GlyfsTer45), and the other results in a 205-bp deletion, leading to delayed termination (p.Phe4149ProfsTer139). Based on the clinical characteristics and gene mutations with functional verification, the patient was finally diagnosed with PKD caused by PKD1 function defection, as confirmed by the combined clinical features and genetic analysis. Management strategies include dietary management, blood pressure monitoring, and regular follow-up of kidney function. This is the first study to report an intronic deletion in the PKD1 gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PKD1-related diseases and highlight the importance of genetic counseling for the family.

多囊蛋白-1（Polycystin-1, PC1）由PKD1基因编码，可与多囊蛋白-2（PKD2；173910）形成复合物，调控多条信号通路以维持正常的肾小管结构与功能。PKD1基因的突变是1型多囊肾病（polycystic kidney disease, PKD）的主要病因，约占所有PKD病例的78%~85%。本研究报道1例男性患儿，临床表现为镜下血尿伴多发肾囊肿，其PKD1基因携带1个未被报道过的内含子变异c.12445-34_12445-10del，该变异遗传自同样患有PKD的父亲。通过桑格测序及迷你基因剪接实验的逆转录聚合酶链式反应（RT-PCR）分析发现，携带该变异的mRNA存在2种异常剪接模式：其一导致第46外显子缺失16 bp，引发蛋白质提前终止（p.Phe4149GlyfsTer45）；其二造成205 bp片段缺失，导致蛋白质翻译延迟终止（p.Phe4149ProfsTer139）。结合该患者的临床特征与基因变异的功能验证结果，最终确诊其为PKD1功能缺陷所致的多囊肾病。该患者的临床管理策略包括饮食管理、血压监测及肾功能定期随访。本研究首次报道了PKD1基因中1个可影响可变剪接的内含子缺失变异。本研究结果拓展了PKD1相关疾病的突变谱，并强调了对该家庭开展遗传咨询的重要性。