title: Mutations in human homologue of chicken talpid3 gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes.
abstract: BACKGROUND
  In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings.
  
  
  METHODS
  In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients.
  
  
  RESULTS
  We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune-Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function.
  
  
  CONCLUSIONS
  Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis.
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, Virginia, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joshi
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Dino
authors.initials: D
authors.lastname: Maglic
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Luhe
authors.initials: L
authors.lastname: Mian
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Konzman
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Guo
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Deniz
authors.initials: D
authors.lastname: Yildirimli
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Bryant
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wadih M
authors.initials: WM
authors.lastname: Zein
authors.affiliation: Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Snow
authors.affiliation: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Meghana
authors.initials: M
authors.lastname: Vemulapalli
authors.affiliation: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.affiliation: Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, Virginia, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Niederhuber
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000002:abnormalities*; D002645:Chickens / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000473:pathology; D004252:DNA Mutational Analysis; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D016368:Frameshift Mutation; D015870:Gene Expression; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008297:Male; D010375:Pedigree; D061251:Primary Cell Culture; D012160:Retina / Q000002:abnormalities*
chemical_list: D018797:Cell Cycle Proteins; C587687:KIAA0586 protein, human
keywords: Clinical genetics; Developmental; ciliopathy; small thorax; whole exome sequencing