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

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...

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Veröffentlicht in:Human molecular genetics 2021-12, Vol.31 (2), p.232-243
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddab239