Background Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism.

Methods We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified.

Results Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes.

Conclusions These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.

背景常染色体显性遗传性多囊肾病（ADPKD）是由PKD1和PKD2突变引起的睫状病变，其特征是肾小管上皮细胞增殖和进行性CKD。尽管尚未建立与囊肿发生有关的分子机制，但已提出在囊上皮细胞中同时激活ADPKD基因的体质和体细胞基因的失活突变是细胞的隐性机制。

方法我们通过全外显子测序（WES）和长距离PCR技术，对9例ADPKD患者的83个肾囊肿的肾上皮细胞中PKD1和PKD2基因的体细胞突变进行了表征，这些患者的PKD1或确定了PKD2。

结果通过远程PCR和WES的完整测序数据分别可用于63个和65个囊肿。在所有患者中以及在分析的90％的囊肿中均发现了PKD1或PKD2的私人体细胞突变。这些突变中有90％是截断，剪接位点或符合预期的致病突变的符合读框的变异。没有发现反式-杂合突变的PKD1或PKD2基因。在12％的囊肿中观察到PKD1的拷贝数变化范围为151 bp至28 kb。WES还发现了53个非PKD1 / 2基因的显着突变，包括其他睫状病变基因和癌症相关基因。

结论这些发现支持ADPKD囊肿形成的细胞隐性机制，主要是由于肾囊肿上皮中PKD1或PKD2的体质和体细胞突变失活引起的。这些基因与其他与纤毛病和癌症相关的基因可能影响ADPKD严重程度的潜在相互作用值得进一步评估。