TY - JOUR
T1 - 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
AU - Caparrós-martín, José A.
AU - De Luca, Alessandro
AU - Cartault, François
AU - Aglan, Mona
AU - Temtamy, Samia
AU - Otaify, Ghada A.
AU - Mehrez, Mennat
AU - Valencia, María
AU - Vázquez, Laura
AU - Alessandri, Jean Luc
AU - Nevado, Julián
AU - Rueda-Arenas, Inmaculada
AU - Heath, Karen E.
AU - Digilio, Maria Cristina
AU - Dallapiccola, Bruno
AU - Goodship, Judith A.
AU - Mill, Pleasantine
AU - Lapunzina, Pablo
AU - Ruiz-Perez, Victor L.
N1 - Publisher Copyright:
© The Author 2015. Published by Oxford University Press. All rights reserved.
PY - 2015/7/15
Y1 - 2015/7/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddv152
DO - 10.1093/hmg/ddv152
M3 - Article
C2 - 25908617
AN - SCOPUS:84936757272
SN - 0964-6906
VL - 24
SP - 4126
EP - 4137
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 14
M1 - ddv152
ER -