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

José A. Caparrós-martín, Alessandro De Luca, François Cartault, Mona Aglan, Samia Temtamy, Ghada A. Otaify, Mennat Mehrez, María Valencia, Laura Vázquez, Jean Luc Alessandri, Julián Nevado, Inmaculada Rueda-Arenas, Karen E. Heath, Maria Cristina Digilio, Bruno Dallapiccola, Judith A. Goodship, Pleasantine Mill, Pablo Lapunzina, Victor L. Ruiz-Perez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)


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.

Original languageEnglish
Article numberddv152
Pages (from-to)4126-4137
Number of pages12
JournalHuman Molecular Genetics
Issue number14
Publication statusPublished - Jul 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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