Invs, also known as Nphp2, encodes the ciliary protein inversin. Mutations in Invs can lead to dysfunction of primary cilia. Invs is significantly associated with nephronophthisis (NPHP), a ciliopathy characterized by renal fibrosis and cyst formation, which is a common cause of end-stage renal disease in children and young adults [1,2].

Global knockout of Invs in mice leads to renal fibrosis and cysts. Epithelial-specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice results in renal cyst formation and severe stromal fibrosis, while Invs deletion in stromal cells (Invsflox/flox;Foxd1-Cre mice) shows no observable phenotypes up to the young adult stage. This highlights the significance of epithelial-stromal crosstalk. Also, increased cell proliferation and myofibroblast activation occur early in disease progression in Invsflox/flox;Cdh16-Cre kidneys, preceding cyst formation. Concomitant removal of cilia partially suppresses the phenotypes of Invsflox/flox;Cdh16-Cre mutant kidneys, indicating an interaction between cilia and Invs function in vivo [1]. In a family with a homozygous INVS mutation, the fetuses had grossly enlarged cystic kidneys, and the mutation led to mislocalization of the mutant inversin protein [2].

In conclusion, Invs plays a critical role in kidney development, especially in maintaining the normal structure and function of renal epithelial cells to prevent NPHP-like phenotypes. Mouse models with Invs knockout or conditional knockout have been instrumental in revealing its role in renal biology and disease, providing insights into the pathogenesis of NPHP and potential therapeutic directions, such as the possible repurposing of valproic acid for NPHP treatment [1].

References:

1. Li, Yuanyuan, Xu, Wenyan, Makova, Svetlana, Brueckner, Martina, Sun, Zhaoxia. 2023. Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse. In eLife, 12, . doi:10.7554/eLife.82395. https://pubmed.ncbi.nlm.nih.gov/36920028/

2. Oud, Machteld M, van Bon, Bregje W, Bongers, Ernie M H F, Roepman, Ronald, Arts, Heleen H. 2014. Early presentation of cystic kidneys in a family with a homozygous INVS mutation. In American journal of medical genetics. Part A, 164A, 1627-34. doi:10.1002/ajmg.a.36501. https://pubmed.ncbi.nlm.nih.gov/24677454/