Nephronophthisis (NPH) is the most prevalent monogenetic disorder leading to end-stage renal failure (ESRD) in childhood. Mutations in Nphp1, encoding a cilia-localized protein, account for the majority of NPH cases. Despite its identification many years ago, Nphp1 deletions targeting exon 4 or exon 20 have not reproduced the histological features of human NPH in murine models. In this study, we deleted exon 2–20 of Nphp1 by CRISPR/Cas9 gene editing to create a near-total knockout (KO) mouse model (Nphp1del2–20/del2–20). Nphp1del2–20/del2–20 mice faithfully reproduced the renal and extrarenal phenotypes associated with human NPH, including renal cyst development, tubular basement membrane thickening, retinal degeneration and abnormal spermatogenesis. Importantly, Nphp1 re-expression using an adenoviral-associated-virus-9 vector could partially rescue both renal and retinal phenotypes in Nphp1del2–20/del2–20 mice. Our results reported the first relevant Nphp1 mouse model with renal phenotypes for human disease. It will be a valuable model for future studies of Nphp1 function and to develop novel treatments for this common childhood disease.

中文翻译：

---

靶向外显子 2-20 的 Nphp1 敲除小鼠模型展示了人类肾痨的特征性表型

肾痨 (NPH) 是最常见的单基因疾病，可导致儿童期终末期肾功能衰竭 (ESRD)。Nphp1 中的突变，编码纤毛定位蛋白，占大多数 NPH 病例。尽管多年前就已鉴定，但针对外显子 4 或外显子 20 的 Nphp1 缺失并未在小鼠模型中重现人类 NPH 的组织学特征。在本研究中，我们通过 CRISPR/Cas9 基因编辑删除了 Nphp1 的外显子 2-20，以创建近乎完全敲除 (KO) 小鼠模型 (Nphp1del2-20/del2-20)。Nphp1del2-20/del2-20 小鼠忠实地再现了与人类 NPH 相关的肾脏和肾外表型，包括肾囊肿发育、肾小管基底膜增厚、视网膜变性和精子发生异常。重要的，使用腺病毒相关病毒 9 载体重新表达 Nphp1 可以部分挽救 Nphp1del2-20/del2-20 小鼠的肾脏和视网膜表型。我们的结果报告了第一个具有人类疾病肾脏表型的相关 Nphp1 小鼠模型。这将成为未来研究 Nphp1 功能的宝贵模型，并为这种常见的儿童疾病开发新的治疗方法。