Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin
Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin
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DOI：
10.1038/ng1520
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发表时间：
2005-03-01
期刊：
影响因子：
30.8
通讯作者：
Hildebrandt, F
中科院分区：
文献类型：
--
作者：
Otto, EA;Loeys, B;Hildebrandt, F
肾病（NPHP）是儿童慢性肾衰竭最常见的遗传原因（1-3）。NPHP 1- 4亚型4个突变基因的鉴定（参考文献）。4- 9)将NPHP的发病机制与纤毛功能联系起来(9)。10%的受影响个体患有视网膜色素变性，构成肾-视网膜老年loken综合征（SLSN）。在这里，我们通过定位克隆确定了进化保守基因IQCB1（也称为NPHP5）的突变是SLSN的最常见原因。IQCB1编码iq结构域蛋白肾囊素-5。所有IQCB1突变的个体都有视网膜色素变性。因此，我们研究了肾囊素-5与RPGR（视网膜色素变性GTPase调节剂）的相互作用，RPGR在光感受器纤毛中表达，与10-20%的视网膜色素变性有关。我们发现肾囊素-5、RPGR和钙调蛋白可以从视网膜提取物中共免疫沉淀，并且这些蛋白定位于光感受器的连接纤毛和肾上皮细胞的原代纤毛。我们的研究强调纤毛功能障碍在SLSN发病机制中的核心作用。
Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children(1-3). Identification of four genes mutated in NPHP subtypes 1- 4 (refs. 4- 9) has linked the pathogenesis of NPHP to ciliary functions(9). Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.