Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium
| Autor: | Ghada A. Otaify, Samia A. Temtamy, Bruno Dallapiccola, Pleasantine Mill, Maria Cristina Digilio, Alessandro De Luca, Laura Vázquez, Victor L. Ruiz-Perez, José A. Caparrós-Martín, Karen E. Heath, Julián Nevado, Judith A. Goodship, Mennat I Mehrez, María Valencia, Pablo Lapunzina, François Cartault, Inmaculada Rueda-Arenas, Mona Aglan, Jean Luc Alessandri |
|---|---|
| Přispěvatelé: | Ministero della Salute, Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2015 |
| Předmět: |
Ellis-Van Creveld Syndrome
Biology Receptors G-Protein-Coupled Exon Intraflagellar transport Genetics medicine Humans Hedgehog Proteins Exome Cilia Molecular Biology Genetics (clinical) Ellis–van Creveld syndrome Cells Cultured Cilium Intracellular Signaling Peptides and Proteins Genetic Variation Infant Proteins Articles General Medicine Exons Fibroblasts medicine.disease Phenotype Smoothened Receptor Pedigree Cytoskeletal Proteins Child Preschool RNA splicing sense organs Smoothened Signal Transduction |
| Zdroj: | Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | et al. Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35−/− cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1−/−, indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35−/− fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc−/− and Evc2−/− mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia. This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-43365-R) and by funding from the Italian Ministry of Health (RF-2010-2310935, RC-2014 to A.D.L.). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|