title: 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.
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.
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain, CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Caparrós-Martín
authors.affiliation: Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.affiliation: CHU de la Réunion Hôpital Félix Guyon, Saint-Denis, Île de la Réunion, France.
authors.forename: François
authors.initials: F
authors.lastname: Cartault
authors.affiliation: Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.affiliation: Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.affiliation: Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Ghada A
authors.initials: GA
authors.lastname: Otaify
authors.affiliation: Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Mennat
authors.initials: M
authors.lastname: Mehrez
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain, CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Valencia
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Vázquez
authors.affiliation: CHU de la Réunion Hôpital Félix Guyon, Saint-Denis, Île de la Réunion, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Alessandri
authors.affiliation: CIBER de Enfermedades Raras (CIBERER), Madrid, Spain, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rueda-Arenas
authors.affiliation: CIBER de Enfermedades Raras (CIBERER), Madrid, Spain, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.affiliation: Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Digilio
authors.affiliation: Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK and.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: Pleasantine
authors.initials: P
authors.lastname: Mill
authors.affiliation: CIBER de Enfermedades Raras (CIBERER), Madrid, Spain, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain, CIBER de Enfermedades Raras (CIBERER), Madrid, Spain, vlruiz@iib.uam.es.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Ruiz-Perez
mesh_terms: D002478:Cells, Cultured; D002675:Child, Preschool; D002923:Cilia / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics*; D059472:Exome; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D014644:Genetic Variation; D053823:Hedgehog Proteins; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor
chemical_list: D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C558596:WDR35 protein, human