Gorden Nicholas T, Arts Heleen H, Parisi Melissa A, Coene Karlien L M, Letteboer Stef J F, van Beersum Sylvia E C, Mans Dorus A, Hikida Abigail, Eckert Melissa, Knutzen Dana, Alswaid Abdulrahman F, Ozyurek Hamit, Dibooglu Sel, Otto Edgar A, Liu Yangfan, Davis Erica E, Hutter Carolyn M, Bammler Theo K, Farin Frederico M, Dorschner Michael, Topçu Meral, Zackai Elaine H, Rosenthal Phillip, Owens Kelly N, Katsanis Nicholas, Vincent John B, Hildebrandt Friedhelm, Rubel Edwin W, Raible David W, Knoers Nine V A M, Chance Phillip F, Roepman Ronald, Moens Cecilia B, Glass Ian A, Doherty Dan
Division of Genetics and Developmental Medicine, Department of Pediatrics, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Am J Hum Genet. 2008 Nov;83(5):559-71. doi: 10.1016/j.ajhg.2008.10.002. Epub 2008 Oct 23.
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 GST pull-down 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.
乔伯特综合征及相关疾病（JSRD）主要为常染色体隐性疾病，其特征为肌张力减退、共济失调、眼球运动异常以及伴有独特中后脑畸形的智力残疾。可变特征包括视网膜营养不良、多囊肾病和肝纤维化。JSRD属于迅速扩大的纤毛病疾病组，因为与JSRD相关的所有六种基因产物（NPHP1、AHI1、CEP290、RPGRIP1L、TMEM67和ARL13B）在初级纤毛/基体细胞器中发挥作用。通过对近亲家庭进行纯合性定位，我们在患有和未患有视网膜、肾脏及肝脏疾病的JSRD患者中鉴定出CC2D2A基因的功能丧失突变。CC2D2A在所有检测的胎儿和成人组织中均有表达。在纤毛细胞中，我们观察到重组CC2D2A定位于基体，并与CEP290共定位，CEP290的同源基因在多种遗传性纤毛病中发生突变。此外，酵母双杂交和GST下拉实验表明，这些蛋白质在体外可发生物理相互作用。斑马鱼CC2D2A直系同源基因（sentinel）中的一个无义突变导致前肾囊肿，这是类似于人类多囊肾病的纤毛功能障碍的一个标志。在sentinel鱼中敲低cep290功能会导致协同的前肾囊肿表型，揭示了CC2D2A与CEP290之间的遗传相互作用，并表明CC2D2A参与纤毛/基体功能。这些观察结果扩展了JSRD的遗传谱，并为研究JSRD和其他纤毛病中的基因外修饰因子提供了一个模型系统。
