Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics
| Autor: | Andreas R. Janecke, Solaf M. Elsayed, Francesca Fabretti, Peter Nürnberg, Ezzat Elsobky, Georg Christoph Korenke, Friederike Koerber, Klaus Addicks, Max C. Liebau, Inga Ebermann, Hanno J. Bolz, Thomas Benzing, Eugen Boltshauser, Claudia Dafinger, Hanswalter Zentgraf, Bernhard Schermer, Yorck Hellenbroich, Gudrun Nürnberg |
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| Přispěvatelé: | University of Zurich, Schermer, B |
| Rok vydání: | 2011 |
| Předmět: |
Male
DNA Mutational Analysis Golgi Apparatus Kinesins 610 Medicine & health 2700 General Medicine Biology Microtubules Retina Joubert syndrome Motor protein Consanguinity Mice Cerebellar Diseases Microtubule Cerebellum Gene duplication medicine Animals Humans Abnormalities Multiple Hedgehog Proteins Tissue Distribution Eye Abnormalities RNA Small Interfering Genetics Chromosomes Human Pair 15 Brief Report Cilium General Medicine Kidney Diseases Cystic medicine.disease Phenotype Hedgehog signaling pathway Pedigree Cell biology 10036 Medical Clinic Kinesin Drosophila Signal Transduction |
| Zdroj: | Journal of Clinical Investigation. 121:2662-2667 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci43639 |
| Popis: | Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS. |
| Databáze: | OpenAIRE |
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