Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic mutations.

Mutations in serologically defined colon cancer autoantigen protein 8 ( ) were first identified in retinal ciliopathy families a decade ago with unknown function. To investigate the pathogenesis of SDCCAG8-associated retinal ciliopathies , we employed CRISPR/Cas9-mediated homology-directed recombination (HDR) to generate two knock-in mouse models, and , which carry truncating mutations of the mouse , corresponding to mutations that cause Bardet-Biedl syndrome (BBS) and Senior-Løken syndrome (SLS) (c.696T>G p.Y232X and c.1339-1340insG p.E447GfsX463) in humans, respectively. The two mutant knock-in mice faithfully recapitulated human SDCCAG8-associated BBS phenotypes such as rod-cone dystrophy, cystic renal disorder, polydactyly, infertility, and growth retardation, with varied age of onset and severity depending on the hypomorphic strength of the mutations. To the best of our knowledge, these knock-in mouse lines are the first BBS mouse models to present with the polydactyly phenotype. Major phototransduction protein mislocalization was also observed outside the outer segment after initiation of photoreceptor degeneration. Impaired cilia were observed in the mutant photoreceptors, renal epithelial cells, and mouse embryonic fibroblasts derived from the knock-in mouse embryos, suggesting that SDCCAG8 plays an essential role in ciliogenesis, and cilium defects are a primary driving force of SDCCAG8-associated retinal ciliopathies.