Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics
Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics
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DOI：
10.1172/jci43639
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发表时间：
2011-07-01
影响因子：
15.9
通讯作者：
Bolz, Hanno Jorn
中科院分区：
文献类型：
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作者：
Dafinger, Claudia;Liebau, Max Christoph;Bolz, Hanno Jorn
Joubert综合征（JBTS）的特征是一种特殊的脑畸形与各种其他病理。它是由至少10种不同基因中的任何一种突变引起的，包括编码肾囊蛋白-1的NPHP 1。JBTS与初级纤毛功能障碍有关，因为已知与该疾病相关的基因产物定位于这种进化上古老的细胞器。在这里，我们报告了一个疾病位点，JBTS 12，在KIF 7基因，果蝇驱动蛋白Costal 2的直系同源基因突变的鉴定，在一个血缘JBTS家庭，随后在其他JBTS患者。有趣的是，KIF 7是一种已知的Hedgehog信号调节因子，也是一种假定的纤毛运动蛋白。我们发现KIF 7与肾囊蛋白-1共沉淀。此外，敲低细胞系中KIF 7表达导致纤毛形成缺陷，并诱导异常中心体复制和高尔基体网络断裂。这些细胞表型可能是由于异常的微管蛋白乙酰化和微管动力学。因此，我们认为KIF 7功能丧失引起的微管稳定性和生长方向改变可能是导致JBTS的潜在疾病机制。
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.