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

作者：Li, Dantong; Hu, Miaoyue; Chen, Huamu; Wu, Xiaohong; Wei, Xiaoya; Lin, Hongrong; Gao, Xuefei; Wang, Haiyan; Li, Min; Ong, Albert C. M.; Yue, Zhihui^*; Sun, Liangzhong^*

来源：Human Molecular Genetics, 2022, 31(2): 232-243.

DOI：10.1093/hmg/ddab239

• FAMILIAL JUVENILE NEPHRONOPHTHISIS
• CHRONIC KIDNEY-DISEASE
• GENE-EXPRESSION
• CANDIDATE GENE
• PROTEIN
• NEPHROCYSTIN
• RENEWAL
• CONSERVATION
• MUTATIONS
• CHILDREN

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.

• 单位
  中山大学; 南方医科大学; 1