Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination
Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination
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DOI：
10.1038/ng1217
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发表时间：
2003-08-01
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;Schermer, B;Hildebrandt, F
肾单位综合征(NPHP)是一种常染色体隐性遗传性囊性肾病，可导致儿童慢性肾功能衰竭。对NPHP1和NPHP4突变基因进行了鉴定，并定位了与婴儿肾炎(NPHP2)相关的基因座。NPHP2的肾脏表型结合了NPHP和多囊肾病(PKD)的临床特征。在这里，我们确定反转蛋白(INVS)是在NPHP2中有和没有反转部位的基因突变。我们展示了逆转酶与肾囊蛋白的分子相互作用，肾囊蛋白是该基因在NPHP1中突变的产物，以及肾囊蛋白与初级纤毛的主要成分β-微管蛋白的相互作用。我们发现肾囊素、反转素和β-微管蛋白共定位于肾小管上皮细胞的初级纤毛。此外，我们通过下调斑马鱼中InVS的表达，产生了一种类似PKD的肾囊性表型和心脏循环的随机化。逆转酶、肾囊素和β-微管蛋白在纤毛中的相互作用和共定位将NPHP的致病方面与PKD、原发纤毛功能和左右轴决定联系在一起。
Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.