Function of NPHP6 a novel gene for Senior-Loken syndrome

Senior-Loken综合征新基因NPHP6的功能

基本信息

批准号：
7020772
负责人：
FRIEDHELM HILDEBRANDT
金额：
$ 34.61万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2009-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Function of NPHP6, a novel gene for Senior-Loken syndrome (nephronophthisis with retinitis pigmentosa). Senior-Loken syndrome (SLS) is characterized by the association of nephronophthisis and retinitis pigmentosa. Nephronophthisis (NPHP) is an autosomal-recessive cystic kidney disease that constitutes the most frequent genetic cause of chronic renal failure in the first two decades of life. We have previously identified by positional cloning the novel genes (NPHP1 and NPHP4) as mutated in NPHP/SLS types 1 and 4, respectively. The NPHP1 gene product, nephrocystin-1, interacts with signaling proteins that regulate actin organization in the cytoskeleton. We have also recently identified by positional cloning the novel gene (NPHP3), mutations in which cause NPHP/SLS type 3. We showed that mutations in its mouse homolog cause the mouse renal cystic phenotype pcy, which was recently shown to be responsive to therapeutic interventions. In addition, we have recently identified mutations in the human inversin gene (INVS) as causing NPHP type 2. The NPHP gene products are expressed in primary cilia of renal tubule cells and in the connecting cilium of the retina. They are part of a novel protein interaction complex. We also showed that the NPHP genes are conserved in the nematode C. elegans. They are expressed in the same specific cilitated neurons that express gene homologs of the autosomal dominant polycystic kidney disease and Bardet-Biedl syndrome genes. Here, we have identified by positional cloning a novel sixth gene (NPHP6) as causing nephronophthisis (NPHP) with retinitis pigmentosa (i.e., Senior-Loken syndrome; SLS type 6). We detected 8 distinct recessive mutations in 12 SLS families in an anonymous gene KIAAO036 (now termed NPHP6). All mutations were truncation mutations. All patients with NPHP6 mutations had NPHP with retinitis pigmentosa. Mutations in NPHP6 were the most frequent cause of SLS. This proposal is aimed at the genetics of NPHP type 6 and at the functional characterization of the novel NPHP6 gene product "nephrocystin-6" that we identified. Specifically, we propose to: 1) Identify further mutations in NPHP6 and study their genotype/phenotype relationships. 2) Characterize the function of the NPHP6 gene and study its role in the pathogenesis of nephronophthisis and retinitis pigmentosa. 3) Generate and characterize mouse models of targeted disruption of the Nphp6 gene. Identification of NPHP6 as a new cause of NPHP and SLS opens new inroads into the understanding of disease mechanisms of renal cystic disease and retinitis pigmentosa.

描述（由申请人提供）：NPHP6的功能，NPHP6的功能，一种新型综合综合征的基因（具有视网膜炎色素炎）。高年级综合征（SLS）的特征在于肾上腺素噬菌体和色素性视网膜炎的关联。肾植物（NPHP）是一种常染色体不必要的囊性肾脏疾病，它构成了生命的前二十年来最常见的慢性肾衰竭遗传原因。我们先前已经通过将新型基因（NPHP1和NPHP4）分别在NPHP/SLS型1和4中突变而识别。 NPHP1基因产物肾环胞菌1与调节细胞骨架中肌动蛋白组织的信号蛋白相互作用。我们最近还通过将新型基因（NPHP3）的位置克隆（引起NPHP/SLS 3型）识别。我们显示其小鼠同源物中的突变导致小鼠肾囊性表型PCY，最近显示出对治疗干预的反应。此外，我们最近将人类inversin基因（Invs）中的突变鉴定为引起NPHP 2型的2型。NPHP基因产物在肾小管细胞的原发性纤毛和视网膜的连接中表达。它们是新型蛋白质相互作用复合物的一部分。我们还表明，NPHP基因在线虫C.秀隐杆线虫中是保守的。它们以相同的特定纤维化神经元表达，这些神经元表达了常染色体显性多囊肾脏疾病和Bardet-Biedl综合征基因的基因同源物。在这里，我们通过将新颖的第六基因（NPHP6）定位为鉴定，导致具有色素性视网膜炎（即，高级言论综合征； SLS 6型）引起肾phronophishisis（NPHP）。我们在一个匿名基因KIAAO036（现称为NPHP6）中检测到了12个SLS家族中的8个不同的隐性突变。所有突变都是截短突变。所有NPHP6突变患者均具有色素性视网膜炎的NPHP。 NPHP6中的突变是SLS的最常见原因。该建议针对NPHP 6型的遗传学以及我们确定的新型NPHP6基因产物“肾上腺囊蛋白6”的功能表征。具体而言，我们建议：1）确定NPHP6中进一步的突变并研究其基因型/表型关系。 2）表征NPHP6基因的功能，并研究其在色素和视网膜炎的发病机理中的作用。 3）生成和表征NPHP6基因靶向破坏的小鼠模型。将NPHP6鉴定为NPHP和SLS的新原因，为了解肾囊性疾病和色素性视网膜炎的疾病机制开辟了新的侵害。