Publication Date:
2015-06-23
Description:
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.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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