Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics
Claudia Dafinger, … , Bernhard Schermer, Hanno Jörn Bolz
Claudia Dafinger, … , Bernhard Schermer, Hanno Jörn Bolz
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2662-2667. https://doi.org/10.1172/JCI43639.
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Brief Report Genetics

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

Claudia Dafinger, Max Christoph Liebau, Solaf Mohamed Elsayed, Yorck Hellenbroich, Eugen Boltshauser, Georg Christoph Korenke, Francesca Fabretti, Andreas Robert Janecke, Inga Ebermann, Gudrun Nürnberg, Peter Nürnberg, Hanswalter Zentgraf, Friederike Koerber, Klaus Addicks, Ezzat Elsobky, Thomas Benzing, Bernhard Schermer, Hanno Jörn Bolz

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Figure 1

KIF7 mutations cause Joubert syndrome and define a novel disease locus, JBTS12.

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KIF7 mutations cause Joubert syndrome and define a novel disease locus,...
For clarity, the one-letter code was applied for mutation designation. (A–C) Pedigrees of JBTS families with KIF7 mutations. (A) Egyptian index family. Linkage analysis in this family identified the 15q locus harboring KIF7. (B) G1 family. Abortion was induced in the first pregnancy because of an encephalocele. (C) G2 family. (D) Top: Axial brain MRIs showing molar tooth sign (red arrow) from the affected members of each family. Bottom: Dysmorphic features characteristic of JBTS (pronounced in E1 and E2, with hexadactyly in E1 and hypertelorism in G1). No dysmorphism in G2. (E) KIF7 gene structure (drawn to scale), mutations, and protein illustration. (F) Expression profile of human and mouse KIF7 (RT-PCR).