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Genetic compensation for cilia defects in cep290/NPHP6 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 (2021). Genetic compensation for cilia defects in cep290/NPHP6 mutants by upregulation of cilia-associated small GTPases. Journal of Cell Science, 134(14):jcs258568.

Abstract

Mutations in CEP290, 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 while defects in a Crispr/Cas9 genetic mutant were restricted to photoreceptor defects. Here we show that milder phenotypes in genetic mutants were associated with 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 JBTS 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.

Abstract

Mutations in CEP290, 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 while defects in a Crispr/Cas9 genetic mutant were restricted to photoreceptor defects. Here we show that milder phenotypes in genetic mutants were associated with 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 JBTS 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > Institute of Medical Genetics
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:15 July 2021
Deposited On:23 Jun 2021 15:37
Last Modified:25 Apr 2024 01:37
Publisher:The Company of Biologists
ISSN:0021-9533
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1242/jcs.258568
PubMed ID:34155518
  • Content: Accepted Version
  • Language: English
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)