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

Author:

Li Dantong1,Hu Miaoyue2,Chen Huamu1,Wu Xiaohong1,Wei Xiaoya1,Lin Hongrong1,Gao Xuefei3,Wang Haiyan4,Li Min1,Ong Albert C M5,Yue Zhihui2,Sun Liangzhong1ORCID

Affiliation:

1. Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

2. Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China

3. Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

4. Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China

5. Kidney Genetics Group, Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, UK

Abstract

Abstract 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.

Funder

National Natural Science Foundations of China

Guangdong Natural Science Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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