Your browser doesn't support javascript.
loading
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.
Afiliación
  • Cardenas-Rodriguez M; Department of Medicine, Nephrology Division, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA.
  • Austin-Tse C; Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay.
  • Bergboer JGM; Department of Pathology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA.
  • Molinari E; Cergentis BV, Yalelaan 62, 3584 CM Utrecht, The Netherlands.
  • Sugano Y; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NE1 3BZ, UK.
  • Bachmann-Gagescu R; Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Sayer JA; Institute of Medical Genetics, University of Zurich Wagistrasse 12, CH-8952 Schlieren, Switzerland.
  • Drummond IA; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NE1 3BZ, UK.
J Cell Sci ; 134(14)2021 07 15.
Article en En | MEDLINE | ID: mdl-34155518
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cilios / Proteínas de Ciclo Celular / Proteínas de Unión al GTP Monoméricas / Proteínas del Citoesqueleto / Antígenos de Neoplasias Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: J Cell Sci Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cilios / Proteínas de Ciclo Celular / Proteínas de Unión al GTP Monoméricas / Proteínas del Citoesqueleto / Antígenos de Neoplasias Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: J Cell Sci Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido