KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.
KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.
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DOI：
10.1186/s13059-015-0858-z
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发表时间：
2015-12-29
期刊：
影响因子：
12.3
通讯作者：
Blacque OE
中科院分区：
文献类型：
--
作者：
Sanders AA;de Vrieze E;Alazami AM;Alzahrani F;Malarkey EB;Sorusch N;Tebbe L;Kuhns S;van Dam TJ;Alhashem A;Tabarki B;Lu Q;Lambacher NJ;Kennedy JE;Bowie RV;Hetterschijt L;van Beersum S;van Reeuwijk J;Boldt K;Kremer H;Kesterson RA;Monies D;Abouelhoda M;Roepman R;Huynen MH;Ueffing M;Russell RB;Wolfrum U;Yoder BK;van Wijk E;Alkuraya FS;Blacque OE
Joubert综合征（JBTS）和相关疾病的定义是小脑畸形（臼齿征），以及不同表现的神经系统症状。Joubert综合征相关疾病的纤毛基础经常将表型扩展到组织，如眼睛、肾脏、骨骼和颅面结构。利用自身基因组和外显子组分析，我们在一个具有轻度Joubert综合征标志性特征的多重血缘家族中发现了KIAA 0556的无效突变。患者来源的成纤维细胞显示纤毛发生能力降低和纤毛异常伸长。疾病病理生理学的研究表明，Kiaa 0556-/- null小鼠具有Joubert综合征相关的脑限制性表型。在秀丽隐杆线虫线虫和培养的人类细胞中的功能研究支持KIAA 0556与微管调节相关的保守纤毛作用。首先，线虫KIAA 0556几乎只在纤毛细胞中表达，并且蠕虫和人KIAA 0556蛋白在纤毛基部富集。第二，C.秀丽线虫KIAA 0056调节纤毛A-小管数量，并与ARL 13 B（JBTS 8）直系同源物遗传相互作用以控制纤毛完整性。第三，人KIAA 0556在体外与微管结合，并且在过表达时似乎稳定微管网络。最后，人KIAA 0556与纤毛蛋白和p60/p80 katanins发生生物化学相互作用。后者形成一种微管切割酶复合物，调节微管动力学以及纤毛功能。我们已经确定KIAA 0556作为一种新的微管相关的睫状碱蛋白突变的Joubert综合征。与轻度患者表型一致，我们的线虫，小鼠和人细胞数据支持KIAA 0556具有相对微妙和可变的纤毛相关功能的概念，我们认为这与微管调节有关。本文的在线版本（doi：10.1186/s13059-015-0858-z）包含补充材料，可供授权用户使用。
Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures. Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556-/- null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions. We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation. The online version of this article (doi:10.1186/s13059-015-0858-z) contains supplementary material, which is available to authorized users.