title: Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.
abstract: 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.
authors.affiliation: Institute of Human Genetics, Department of Medicine and Centre for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dafinger
authors.forename: Max Christoph
authors.initials: MC
authors.lastname: Liebau
authors.forename: Solaf Mohamed
authors.initials: SM
authors.lastname: Elsayed
authors.forename: Yorck
authors.initials: Y
authors.lastname: Hellenbroich
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.forename: Georg Christoph
authors.initials: GC
authors.lastname: Korenke
authors.forename: Francesca
authors.initials: F
authors.lastname: Fabretti
authors.forename: Andreas Robert
authors.initials: AR
authors.lastname: Janecke
authors.forename: Inga
authors.initials: I
authors.lastname: Ebermann
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Hanswalter
authors.initials: H
authors.lastname: Zentgraf
authors.forename: Friederike
authors.initials: F
authors.lastname: Koerber
authors.forename: Klaus
authors.initials: K
authors.lastname: Addicks
authors.forename: Ezzat
authors.initials: E
authors.lastname: Elsobky
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Hanno Jörn
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000015:Abnormalities, Multiple; D000818:Animals; D002526:Cerebellar Diseases / Q000235:genetics* / Q000503:physiopathology; D002531:Cerebellum / Q000002:abnormalities; D002884:Chromosomes, Human, Pair 15; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics* / Q000503:physiopathology; D006056:Golgi Apparatus / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000503:physiopathology; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D010375:Pedigree; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000002:abnormalities / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D014018:Tissue Distribution
chemical_list: D053823:Hedgehog Proteins; C502069:KIF7 protein, human; D034741:RNA, Small Interfering; C509239:SHH protein, human; D016547:Kinesins