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Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Lookup NU author(s): Dr Elisa MolinariORCiD, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021. Published by The Company of Biologists Ltd.Mutations in CEP290 (also known as NPHP6), a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish, the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes, whereas deficiencies in a CRISPR/Cas9 genetic mutant were restricted to photoreceptor defects. Here, we show that milder phenotypes in genetic mutants were associated with the upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human Joubert syndrome CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies.

Publication metadata

Author(s): Cardenas-Rodriguez M, Austin-Tse C, Bergboer JGM, Molinari E, Sugano Y, Bachmann-Gagescu R, Sayer JA, Drummond IA

Publication type: Article

Publication status: Published

Journal: Journal of Cell Science

Year: 2021

Volume: 134

Issue: 14

Print publication date: 01/07/2021

Online publication date: 22/07/2021

Acceptance date: 02/06/2021

Date deposited: 27/08/2021

ISSN (print): 0021-9533

ISSN (electronic): 1477-9137

Publisher: Company of Biologists Ltd


DOI: 10.1242/jcs.258568

PubMed id: 34155518


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