Dataset Information

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.

SUBMITTER: Malicdan MC

PROVIDER: S-EPMC5517294 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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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.

Malicdan May Christine V MC Vilboux Thierry T Stephen Joshi J Maglic Dino D Mian Luhe L Konzman Daniel D Guo Jennifer J Yildirimli Deniz D Bryant Joy J Fischer Roxanne R Zein Wadih M WM Snow Joseph J Vemulapalli Meghana M Mullikin James C JC Toro Camilo C Solomon Benjamin D BD Niederhuber John E JE Gahl William A WA Gunay-Aygun Meral M

Journal of medical genetics 20150918 12

<h4>Background</h4>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.<h4>Methods</h4>In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive c ...[more]

PMID: 26386044

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Project description:Joubert syndrome (JS) is a ciliopathy associated with mutations in numerous genes encoding cilia components. TALPID3 encoded by KIAA0856 in man (2700049A03Rik in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in KIAA0856 have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11-12 of Talpid3 in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. Talpid3 mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre-derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in Wnt7a expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of Talpid3. The Talpid3 conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for Talpid3 in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

Mutations in human homologue of chicken talpid3 gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes.

Publications

Mutations in human homologue of chicken talpid3 gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes.

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