Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants.

Disease models & mechanisms 2022 Dec 01

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Meckel syndrome, nephronophthisis, Joubert syndrome and Bardet-Biedl syndrome are caused by mutations in proteins that localize to the ciliary transition zone (TZ). The phenotypically distinct syndromes suggest that these TZ proteins have differing functions. However, mutations in a single TZ gene can result in multiple syndromes, suggesting that the phenotype is influenced by modifier genes. We performed a comprehensive analysis of ten zebrafish TZ mutants, including mks1, tmem216, tmem67, rpgrip1l, cc2d2a, b9d2, cep290, tctn1, nphp1 and nphp4, as well as mutants in ift88 and ift172. Our data indicate that variations in phenotypes exist between different TZ mutants, supporting different tissue-specific functions of these TZ genes. Further, we observed phenotypic variations within progeny of a single TZ mutant, reminiscent of multiple disease syndromes being associated with mutations in one gene. In some mutants, the dynamics of the phenotype became complex with transitory phenotypes that are corrected over time. We also demonstrated that multiple-guide-derived CRISPR/Cas9 F0 'crispant' embryos recapitulate zygotic null phenotypes, and rapidly identified ciliary phenotypes in 11 cilia-associated gene candidates (ankfn1, ccdc65, cfap57, fhad1, nme7, pacrg, saxo2, c1orf194, ttc26, zmynd12 and cfap52). © 2022. Published by The Company of Biologists Ltd.

Citation

Jun Wang, Holly R Thomas, Robert G Thompson, Stephanie C Waldrep, Joseph Fogerty, Ping Song, Zhang Li, Yongjie Ma, Peu Santra, Jonathan D Hoover, Nan Cher Yeo, Iain A Drummond, Bradley K Yoder, Jeffrey D Amack, Brian Perkins, John M Parant. Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. Disease models & mechanisms. 2022 Dec 01;15(12)