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Mutations in human homologue of chicken talpid3 gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes
  1. May Christine V Malicdan1,2,
  2. Thierry Vilboux2,3,
  3. Joshi Stephen2,
  4. Dino Maglic2,
  5. Luhe Mian2,
  6. Daniel Konzman2,
  7. Jennifer Guo2,
  8. Deniz Yildirimli2,
  9. Joy Bryant2,
  10. Roxanne Fischer2,
  11. Wadih M Zein4,
  12. Joseph Snow5,
  13. Meghana Vemulapalli6,
  14. James C Mullikin6,
  15. Camilo Toro1,
  16. Benjamin D Solomon3,
  17. John E Niederhuber8,
  18. NISC Comparative Sequencing Program6,
  19. William A Gahl1,2,7,
  20. Meral Gunay-Aygun2,7
  1. 1NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  3. 3Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, Virginia, USA
  4. 4Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
  5. 5Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA
  6. 6NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  7. 7Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  8. 8Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA
  1. Correspondence to Dr Meral Gunay-Aygun, National Human Genome Research Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Rm 10C103C, Bethesda, MD 20892-1851, USA; mgaygun{at}mail.nih.gov

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.

  • ciliopathy
  • Clinical genetics
  • Developmental
  • whole exome sequencing
  • small thorax

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