CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290
CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290
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DOI：
10.1016/j.ajhg.2008.10.002
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发表时间：
2008-11-07
影响因子：
9.8
通讯作者：
Doherty, Dan
中科院分区：
文献类型：
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作者：
Gorden, Nicholas T.;Arts, Heleen H.;Doherty, Dan
Joubert综合征及相关疾病（JSRD）主要是常染色体隐性遗传疾病，其特征为张力减退、共济失调、眼球运动异常和伴有明显中后脑畸形的智力残疾。可变特征包括视网膜营养不良、囊性肾病和肝纤维化。JSRD）被包括在称为纤毛病的快速扩展的疾病组中，因为涉及JSRD的所有六种基因产物（NPHP 1、AHI 1、CEP 290、RPGRIP 1 L、TMEM 67和ARL 13 B）在初级纤毛/基体细胞器中起作用。通过在血缘家族中进行纯合性定位，我们鉴定了有或无视网膜、肾脏和肝脏疾病的JSRD患者中CC 2D 2A的功能缺失突变。CC 2D 2A在所有测试的胎儿和成人组织中表达。在纤毛细胞中，我们观察到重组CC 2D 2A在基体的定位和与CEP 290的共定位，CEP 290的同源基因在多发性遗传性纤毛病中发生突变。此外，蛋白质可以在体外物理相互作用，如酵母双杂交和GST下拉实验所示。斑马鱼CC 2D 2A直系同源物（哨兵）中的无义突变导致原肾囊肿，这是类似于人类囊性肾病的纤毛功能障碍的标志。敲低cep 290功能的哨兵鱼的结果在一个协同的前肾囊肿表型，揭示了CC 2D 2A和CEP 290之间的遗传相互作用，并牵连CC 2D 2A纤毛/基体功能。这些观察结果扩展了JSRD的遗传谱，并为研究JSRD和其他纤毛虫病中的基因外修饰剂提供了模型系统。
Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD) are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function Mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GSTpulldown experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for Studying extragenic modifiers in JSRD and other ciliopathies.