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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

Lookup NU author(s): Professor Judith Goodship

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Abstract

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.


Publication metadata

Author(s): Caparros-Martin JA, De Luca A, Cartault F, Aglan M, Temtamy S, Otaify GA, Mehrez M, Valencia M, Vazquez L, Alessandri JL, Nevado J, Rueda-Arenas I, Heath KE, Digilio MC, Dallapiccola B, Goodship JA, Mill P, Lapunzina P, Ruiz-Perez VL

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2015

Volume: 24

Issue: 14

Pages: 4126-4137

Print publication date: 15/07/2015

Online publication date: 23/04/2015

Acceptance date: 21/04/2015

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/hmg/ddv152

DOI: 10.1093/hmg/ddv152


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Funding

Funder referenceFunder name
HL-102923NHLBI NIH HHS
HL-102924NHLBI NIH HHS
HL-102926NHLBI NIH HHS
HL-103010NHLBI NIH HHS
HL-102925NHLBI NIH HHS
MC_UU_12018/26Medical Research Council
RC2 HL102923NHLBI NIH HHS
RC2 HL102926NHLBI NIH HHS
RC2 HL103010NHLBI NIH HHS
UC2 HL102924NHLBI NIH HHS
UC2 HL102926NHLBI NIH HHS
UC2 HL103010NHLBI NIH HHS
RC2 HL102924NHLBI NIH HHS
RC2 HL102925NHLBI NIH HHS
UC2 HL102923NHLBI NIH HHS
UC2 HL102925NHLBI NIH HHS

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