1. ABSTRACT Novel genetics, pathobiology, and therapy of nephronophthisis-related ciliopathies (NPHP-RC). Nephronophthisis-related ciliopathies (NPHP-RC) are recessive cystic kidney diseases that cause chronic kidney disease (CKD) in the first 30 years of life. They can be associated with retinal degeneration, liver fibrosis, skeletal and brain malformations. No treatment exists for NPHP-RC. Using genetic mapping and whole exome sequencing, we discovered, functionally characterized and published 46 of the ~100 genes currently known to cause NPHP-RC, if mutated. Gene discovery lead to the following insights: i) the ?ciliopathy theory? of cystic kidney diseases; ii) discovery that the pathogenesis of NPHP-RC involves mechanisms of non-canonical Wnt signaling, planar cell polarity, sonic hedgehog signaling, aspects of cell cycle regulation; iii) generation of mouse and zebrafish models of NPHP-RC; iv) , and v) the realization that syndromic developmental forms of NPHP-RC are primarily caused by null mutations, whereas degene- rative forms are preferentially caused by hypomorphic mutations in the same NPHP-RC genes. We also showed that with ~100 NPHP-RC genes identified, the encoded NPHP-RC proteins cluster within specific centrosomal/ciliary protein interaction complexes that partially correlate with disease phenotypes. We developed a high-throughput sequencing system that allows rapid mutation analysis of all ~100 known NPHP-RC genes, demonstrating in a worldwide cohort of 1,540 families with NPHP-RC that mutations in known genes only explain ~50% of all cases and that many additional NPHP-RC genes must exist. In the last 3 years, we discovered, characterized and published 11 novel NPHP-RC genes. Very recently, by identifying recessive mutations in MAP7D3 and TTC28 as causing NPHP-RC, we revealed centrosomal/ciliary protein interaction clusters relevant for ciliary length control as related to the pathogenesis of NPHP-RC. To discover the missing NPHP-RC genes, to delineate the associated signaling mechanisms, and to generate develop therapeutic options using animal models, we now propose to: SA1. Identify and functionally characterize the missing components of NPHP-related ciliopathies by whole exome/genome sequencing, CNV and mRNAseq analysis in ~1,500 families with NPHP-RC. SA2. Characterize disease mechanisms for the newly identified NPHP-RC genes MAP7D3 and TTC28 that participate in a shared centrosomal module. SA3. Utilize zebrafish models for allele validation, to delineate pathogenic pathways, and to develop first treatment options for NPHP-RC. 1
Nephronophthisis-related ciliopathies (NPHP-RC), a genetic cause of chronic kidney disease, are associated with blindness, liver fibrosis, and organ malformations. No specific treatment is available. Previous gene identification helped define the new disease group of ?ciliopathies,? caused by loss of function of primary cilia, which are antenna-like structures that are used by cells in the body for tissue development and repair. We will continue to discover novel genetic causes of NPHP-RC genes and develop animal models of disease, to generate further insights into disease mechanisms of NPHP-RC and develop novel therapeutic approaches to these chronic kidney diseases.
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