The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin
The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin
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DOI：
10.1038/ng996
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发表时间：
2002-10-01
期刊：
影响因子：
30.8
通讯作者：
Saunier, S
中科院分区：
文献类型：
--
作者：
Mollet, G;Salomon, R;Saunier, S
肾炎是儿童慢性肾功能衰竭最常见的遗传原因，是一种进行性肾小管间质疾病，遗传为常染色体隐性遗传。该病的特点是在儿童或青春期出现多尿、生长迟缓和肾功能恶化。最显著的组织学特征是肾小管改变，基底膜增厚，间质纤维化，晚期可见髓囊肿(1)。肾炎也可与影响肾外器官的情况有关，如视网膜色素变性(High-Loken综合征)(2，3)和眼运动性失用(Cogan综合征)(4)。在染色体2q13(NPHP1；参考文献5，6)、9q22(NPHP2；参考文献5，6)上，有三个基因座与幼年期、婴儿型和青春型相关。7)和3q21(NPHP3；参考文献8)。NPHP1是目前已发现的唯一编码肾囊藻毒素(9，10)的基因，它含有一个Src同源3(SH3)结构域，并与参与细胞黏附的胞浆内蛋白相互作用(11-13)。最近，与该病幼年型相关的第二个基因座NPHP4被定位到染色体1p36(参考文献1)。14)。我们使用覆盖该区域的标记，对与NPHP1、NPHP2或NPHP3基因座没有关联的肾单位病家系进行了单倍型分析。这使得我们可以将NPHP4的间隔减少到D1S2795和D1S2870之间的1厘米，D1S2870包含6个基因。我们在其中一个基因中发现了五种不同的突变，命名为NPHP4，在患有肾炎的无关个体中。NPHP4基因编码1,250个氨基酸的未知功能蛋白，我们将其命名为肾囊藻毒素-4。我们证实了肾囊藻蛋白-4与肾囊藻毒素的相互作用，表明这两种蛋白参与了共同的信号通路。
Nephronophthisis, the most common genetic cause of chronic renal failure in children, is a progressive tubulo-interstitial kidney disorder that is inherited as an autosomal recessive trait. The disease is characterized by polyuria, growth retardation and deterioration of renal function during childhood or adolescence. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts(1). Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (Senior-Loken syndrome) (2,3) and ocular motor apraxia (Cogan syndrome)(4). Three loci are associated with the juvenile, infantile and adolescent forms, on chromosomes 2q13 (NPHP1; refs 5,6), 9q22 (NPHP2; ref. 7) and 3q21 (NPHP3; ref. 8), respectively. NPHP1, the only gene identified so far, encodes nephrocystin(9,10), which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion (11-13). Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14). We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region. This allowed us to reduce the NPHP4 interval to a one centimorgan interval between D1S2795 and D1S2870, which contains six genes. We identified five different mutations in one of these genes, designated NPHP4, in unrelated individuals with nephronophthisis. The NPHP4 gene encodes a 1,250-amino acid protein of unknown function that we named nephrocystin-4. We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway.