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

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 dis...

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Autores principales: Cardenas-Rodriguez, Magdalena, Austin-Tse, Christina, Bergboer, Judith G. M., Molinari, Elisa, Sugano, Yuya, Bachmann-Gagescu, Ruxandra, Sayer, John A., Drummond, Iain A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325957/
https://www.ncbi.nlm.nih.gov/pubmed/34155518
http://dx.doi.org/10.1242/jcs.258568
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author Cardenas-Rodriguez, Magdalena
Austin-Tse, Christina
Bergboer, Judith G. M.
Molinari, Elisa
Sugano, Yuya
Bachmann-Gagescu, Ruxandra
Sayer, John A.
Drummond, Iain A.
author_facet Cardenas-Rodriguez, Magdalena
Austin-Tse, Christina
Bergboer, Judith G. M.
Molinari, Elisa
Sugano, Yuya
Bachmann-Gagescu, Ruxandra
Sayer, John A.
Drummond, Iain A.
author_sort Cardenas-Rodriguez, Magdalena
collection PubMed
description 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.
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spelling pubmed-83259572021-08-12 Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases Cardenas-Rodriguez, Magdalena Austin-Tse, Christina Bergboer, Judith G. M. Molinari, Elisa Sugano, Yuya Bachmann-Gagescu, Ruxandra Sayer, John A. Drummond, Iain A. J Cell Sci Research Article 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. The Company of Biologists Ltd 2021-07-22 /pmc/articles/PMC8325957/ /pubmed/34155518 http://dx.doi.org/10.1242/jcs.258568 Text en © 2021. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Cardenas-Rodriguez, Magdalena
Austin-Tse, Christina
Bergboer, Judith G. M.
Molinari, Elisa
Sugano, Yuya
Bachmann-Gagescu, Ruxandra
Sayer, John A.
Drummond, Iain A.
Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases
title Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases
title_full Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases
title_fullStr Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases
title_full_unstemmed Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases
title_short Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases
title_sort genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small gtpases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325957/
https://www.ncbi.nlm.nih.gov/pubmed/34155518
http://dx.doi.org/10.1242/jcs.258568
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