Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia
Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia
复制标题
DOI：
10.1681/asn.2005121351
复制
发表时间：
2006-09-01
影响因子：
13.6
通讯作者：
Omran, Heymut
中科院分区：
文献类型：
--
作者：
Fliegauf, Manfred;Horvath, Judit;Omran, Heymut
肾病综合征（NPHP）是一种遗传性囊性肾疾病，可导致儿童和年轻人肾衰竭，并可能与各种肾外疾病，包括视网膜色素变性。已经鉴定出6个NPHP基因，其功能被NPHP患者的常染色体隐性突变破坏。大多数NPHP患者携带编码肾囊素的NPHP1纯合缺失。先前的数据表明肾囊蛋白在细胞连接处和粘着斑处形成复合物。在这里，它表明，肾囊蛋白特异性地定位在纤毛基部的过渡区的肾和呼吸纤毛和感光器连接纤毛。在原代人呼吸道上皮细胞的体外纤毛发生过程中，肾囊蛋白可以检测到第一个弥漫性细胞质定位，只要细胞极化开始，并易位到过渡区时，纤毛形成。在柱状呼吸细胞中，肾囊蛋白在包含钙敏感纤毛自切位点的区域紧密地附着于过渡区的轴丝结构。在纯合子NPHP1缺失的患者中，肾囊蛋白在整个呼吸细胞中缺失，包括过渡区，这可能是未来诊断方法的兴趣。纤毛的形成没有改变，在初级肾胱氨酸缺乏的呼吸细胞，这是与以前的研究结果获得的秀丽隐杆线虫直系同源物。此外，它表明，鞭毛内转运蛋白和肾囊素的本地化模式不同，提示不同的功能作用。总之，肾单纤毛过渡区和连接纤毛的光感受器的肾囊素缺乏或功能障碍可能解释NPHP1患者中观察到的肾衰竭和视网膜变性。
Nephronophthisis (NPHP) is a hereditary cystic kidney disorder that causes renal failure in children and young adults and can be associated with various extrarenal disorders, including retinitis pigmentosa. Six NPHP genes, whose functions are disrupted by autosomal recessive mutations in patients with NPHP, have been identified. The majority of patients with NPHP carry homozygous deletions of NPHP1 encoding nephrocystin. Previous data indicate that nephrocystin forms a complex at cell junctions and focal adhesions. Here, it is shown that nephrocystin specifically localizes at the ciliary base to the transition zone of renal and respiratory cilia and to photoreceptor connecting cilia. During in vitro ciliogenesis of primary human respiratory epithelial cells, nephrocystin can be detected first with a diffuse cytoplasmic localization as soon as cell polarization starts, and translocates to the transition zone when cilia are formed. In columnar respiratory cells, nephrocystin is attached tightly to the axonemal structure of the transition zone at a region that contains the calcium-sensitive cilia autotomy site. In patients with homozygous NPHP1 deletions, nephrocystin is absent from the entire respiratory cell, including the transition zone, which might be of interest for future diagnostic approaches. Cilia formation is not altered in primary nephrocystin-deficient respiratory cells, which is consistent with previous findings obtained for the Caenorhabditis elegans ortholog. In addition, it is shown that the localization pattern of intraflagellar transport proteins and nephrocystin differs, suggesting distinct functional roles. In conclusion, nephrocystin deficiency or dysfunction at the transition zone of renal monocilia and the photoreceptor connecting cilium might explain renal failure and retinal degeneration that are observed in patients with NPHP1.