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Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases.
- Source :
-
Journal of cell science [J Cell Sci] 2021 Jul 15; Vol. 134 (14). Date of Electronic Publication: 2021 Jul 22. - Publication Year :
- 2021
-
Abstract
- 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. This article has an associated First Person interview with the first author of the paper.<br />Competing Interests: Competing interests The authors declare no competing or financial interests.<br /> (© 2021. Published by The Company of Biologists Ltd.)
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Humans
Microtubule-Associated Proteins
Mutation genetics
Up-Regulation genetics
Zebrafish genetics
Zebrafish metabolism
Zebrafish Proteins genetics
Zebrafish Proteins metabolism
Antigens, Neoplasm genetics
Cell Cycle Proteins genetics
Cilia genetics
Cilia metabolism
Cytoskeletal Proteins genetics
Monomeric GTP-Binding Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9137
- Volume :
- 134
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of cell science
- Publication Type :
- Academic Journal
- Accession number :
- 34155518
- Full Text :
- https://doi.org/10.1242/jcs.258568