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. ? ?
| Davis, Erica E; Zhang, Qi; Liu, Qin et al. (2011) TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 43:189-96 |
| Hildebrandt, Friedhelm; Benzing, Thomas; Katsanis, Nicholas (2011) Ciliopathies. N Engl J Med 364:1533-43 |
| Hoefele, Julia; Nayir, Ahmet; Chaki, Moumita et al. (2011) Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion. Pediatr Nephrol 26:967-71 |
| Wolf, Matthias T F; Hildebrandt, Friedhelm (2011) Nephronophthisis. Pediatr Nephrol 26:181-94 |
| Otto, Edgar A; Ramaswami, Gokul; Janssen, Sabine et al. (2011) Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy. J Med Genet 48:105-16 |
| Zhou, Weibin; Dai, Julie; Attanasio, Massimo et al. (2010) Nephrocystin-3 is required for ciliary function in zebrafish embryos. Am J Physiol Renal Physiol 299:F55-62 |
| Harville, H M; Held, S; Diaz-Font, A et al. (2010) Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. J Med Genet 47:262-7 |
| Zaucke, Frank; Boehnlein, Joana M; Steffens, Sarah et al. (2010) Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression. Hum Mol Genet 19:1985-97 |
| Hildebrandt, Friedhelm; Attanasio, Massimo; Otto, Edgar (2009) Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 20:23-35 |
| Hildebrandt, Friedhelm; Heeringa, Saskia F; Rüschendorf, Franz et al. (2009) A systematic approach to mapping recessive disease genes in individuals from outbred populations. PLoS Genet 5:e1000353 |
Showing the most recent 10 out of 18 publications
