title: Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60.
abstract: Short-rib polydactyly syndromes (SRPS I-V) are a group of lethal congenital disorders characterized by shortening of the ribs and long bones, polydactyly, and a range of extraskeletal phenotypes. A number of other disorders in this grouping, including Jeune and Ellis-van Creveld syndromes, have an overlapping but generally milder phenotype. Collectively, these short-rib dysplasias (with or without polydactyly) share a common underlying defect in primary cilium function and form a subset of the ciliopathy disease spectrum. By using whole-exome capture and massive parallel sequencing of DNA from an affected Australian individual with SRPS type III, we detected two novel heterozygous mutations in WDR60, a relatively uncharacterized gene. These mutations segregated appropriately in the unaffected parents and another affected family member, confirming compound heterozygosity, and both were predicted to have a damaging effect on the protein. Analysis of an additional 54 skeletal ciliopathy exomes identified compound heterozygous mutations in WDR60 in a Spanish individual with Jeune syndrome of relatively mild presentation. Of note, these two families share one novel WDR60 missense mutation, although haplotype analysis suggested no shared ancestry. We further show that WDR60 localizes at the base of the primary cilium in wild-type human chondrocytes, and analysis of fibroblasts from affected individuals revealed a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme. These findings show that WDR60 mutations can cause skeletal ciliopathies and suggest a role for WDR60 in ciliogenesis.
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Level 7, 37 Kent Street, Woolloongabba, QLD 4102, Australia.
authors.forename: Aideen M
authors.initials: AM
authors.lastname: McInerney-Leo
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Claudio R
authors.initials: CR
authors.lastname: Cortés
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: Blanca
authors.initials: B
authors.lastname: Gener
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Courtney
authors.forename: Brooke
authors.initials: B
authors.lastname: Gardiner
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Harris
authors.forename: Yeping
authors.initials: Y
authors.lastname: Lu
authors.forename: Mhairi
authors.initials: M
authors.lastname: Marshall
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.forename: Carol
authors.initials: C
authors.lastname: Wicking
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002675:Child, Preschool; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D020090:Chromosome Segregation / Q000235:genetics; D002923:Cilia / Q000378:metabolism; D004613:Ellis-Van Creveld Syndrome / Q000000981:diagnostic imaging / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005333:Fetus / Q000000981:diagnostic imaging; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D011859:Radiography; D012779:Short Rib-Polydactyly Syndrome / Q000000981:diagnostic imaging / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050505:Mutant Proteins; C584144:DYNC2I1 protein, human
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