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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 ( Nphp1 del2–20/del2–20  ).  Nphp1 del2–20/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  Nphp1 del2–20/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.

An Nphp1 knockout mouse model targeting exon 2–20 demonstrates characteristic phenotypes of human nephronophthisis