Cited by 57Genetic and Kidney Cyst DiseasesCystic Fibrosis Research AdvancesHedgehog Signaling Pathway Studies

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

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Caparrós-Martín, José A., De Luca, Alessandro, Cartault, François, Aglan, Mona, Temtamy, Samia, Otaify, Ghada A., Mehrez, Mennat, Valencia, María +11 more·2015·Human Molecular Genetics

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.

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Crossref · 10.1093/hmg/ddv152

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  • The IFT-A complex interacts with the tubby domain proteins TULP3 and TUB to mediate ciliary targeting of certain transmembrane proteins, including G protein-coupled receptors.

    “Furthermore, the IFT-A complex interacts with the tubby domain proteins TULP3 and TUB to mediate ciliary targeting of certain transmembrane proteins, including G protein-coupled receptors (GPCRs) 56, 58, 64–69.”

    From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [69]

    The Discussion (p. 9) says IFT-A helps translocate membrane proteins, including SMO, into cilia, and the results (p. 5) show that ciliary entry of EVC, EVC2 and SMO requires an IFT-A subunit. Our copy does not say that IFT-A interacts with TULP3 or the tubby-domain protein TUB, or that such an interaction mediates this targeting. (LLM, conf=0.85)

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  1. [22]22. Arts, H. and Knoers, N. (2013) Cranioectodermal dysplasia. In Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya, A., Bean, L.J.H., Bird, T.D., Dolan, C.R., Fong, C.T., Smith, R.J.H. and Stephens, K. (eds). GeneReviews® [Internet] , University of Washington, Seattle, WA, pp. 1993 -2015, http://www.ncbi.nlm.nih.gov/books/NBK154653/.

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Authors
Caparrós-Martín, J. A., De Luca, A., Cartault, F., Aglan, M., Temtamy, S., Otaify, G. A., Mehrez, M., Valencia, M., Vázquez, L., Alessandri, J.-L., Nevado, J., Rueda-Arenas, I., Heath, K. E., Digilio, M. C., Dallapiccola, B., Goodship, J. A., Mill, P., Lapunzina, P., & Ruiz-Perez, V. L.
Affiliations
  • Centre Hospitalier Universitaire de La Réunion (RE)
  • National Research Centre (EG)
  • Consejo Superior de Investigaciones Científicas (ES)
  • Hospital Universitario La Paz (ES)
  • Bambino Gesù Children's Hospital (IT)
  • Newcastle University (GB)
  • Western General Hospital (GB)
Venue
Human Molecular Genetics
Published
2015-04-23
Volume
24
Issue
14
Pages
4126-4137
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2107338226
Cited by
57
References
45
Citations by year
2026: 3 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 8 · 2019: 3 · 2018: 4 · 2017: 11 · 2016: 5 · 2015: 1
FWCI
4.81
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • eSpace (Curtin University) (submittedVersion)
Funders
  • University of Georgia
  • National Institutes of Health (1rc2hl103010-01)
  • National Heart, Lung, and Blood Institute (HL 102923, RC2HL102925, HL-102924, HL-102925, RC2HL102926, RC2HL102923, UC2HL102924, RC2HL-103010, UC2HL102925, HL 103010, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926, HL-102926)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Keywords
Ellis-van Creveld syndrome, splice variants, ciliary transport, IFT-A complex, EVC2, Smoothened, Hedgehog signaling, genetic heterogeneity, DYNC2H1
MeSH terms
Smoothened Receptor, Cells, Cultured, Child, Preschool, Cilia, Cytoskeletal Proteins, Ellis-Van Creveld Syndrome, Exons, Fibroblasts, Humans, Infant, Pedigree, Phenotype, Proteins, Genetic Variation, Signal Transduction, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Hedgehog Proteins, Exome

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