title: WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia.
abstract: Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies.
authors.affiliation: Department of Genetics, INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris 75015, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Sulin
authors.initials: S
authors.lastname: Wu
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Kim
authors.forename: Sabine
authors.initials: S
authors.lastname: Sigaudy
authors.forename: Anna
authors.initials: A
authors.lastname: Sarukhanov
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Genevieve
authors.initials: G
authors.lastname: Baujat
authors.forename: Kim-Hanh
authors.initials: KH
authors.lastname: Le Quan Sang
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002923:Cilia / Q000235:genetics* / Q000473:pathology; D056445:Cytoplasmic Dyneins / Q000235:genetics; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism*; D012272:Ribs / Q000002:abnormalities / Q000473:pathology; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; C099883:DYNC2H1 protein, human; C530863:IFT80 protein, human; D016328:NF-kappa B; C543203:WDR34 protein, human; D056445:Cytoplasmic Dyneins