Nephronophthisis (NPHP) is a monogenic recessive cystic kidney disease that represents the most frequent genetic cause of kidney failure in the first 30 years of life. It can be associated with progressive blindness (retinal degeneration), liver fibrosis, mental retardation and malformations of brain, heart and bone. By homozygosity mapping we have previously identified recessive mutations in 4 genes (NPHP1-4) as the cause of NPHP with retinal involvement. Within the preceding award we identified and characterized 5 additional NPHP-causing genes (NPHP5-9) and generated disease models in mouse and zebrafish. The data helped define a unifying pathogenic concept for the new disease entity of "ciliopathies", which represent genetic defects in functional components of primary cilia (PC). PC are sensory organelles expressed by virtually all vertebrate cell types. PC are utilized across evolution, from single cellular organisms to humans, for cellular sensory tasks, including photo-, mechano-, thermo-, olfactory, and hormonal sensation. By identification of the NPHP1-9 genes we implicated non-canonical Wnt signaling, hedgehog signaling, and cell cycle regulation in the pathogenesis of cystic kidney diseases. In addition, we demonstrated that specific mutated alleles determine the disease phenotype of NPHP-related ciliopathies in the following way: Two truncating mutations cause a severe, early- onset developmental phenotype that affects morphogenesis and leads to malformation or dysplasia (Meckel- Gruber syndrome), whereas two missense mutations cause only a mild, late-onset mature tissue phenotype that affects tissue maintenance and repair and leads to degeneration and premature ageing of organs (Senior- Loken syndrome). We demonstrate in a worldwide cohort of 1,500 families with NPHP-related ciliopathies that mutations in NPHP1-9 only explain 30% of all cases and that many additional disease causing genes must exist. To discover new ciliopathy genes and the associated signaling mechanisms, and to generate animal models and therapeutic options, we propose to: 1. Identify and functionally characterize novel genes that cause NPHP-related ciliopathies, if mutated. 2. Functionally characterize novel ciliopathy genes and determine genotype-phenotype correlations. 3. Use zebrafish models to study the function of novel genes identified and to test new drugs.

Public Health Relevance

Nephronophthisis (NPHP), a genetic cause of chronic kidney disease, is 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 sensory organelles important for photo-, mechano-, and olfactory sensation and for tissue development and repair. Identification of novel NPHP-related ciliopathy genes will provide further insights into disease mechanisms of dysplastic and degenerative diseases of multiple organs. It will allow development of animal models and novel therapeutic approaches to these degenerative diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Rasooly, Rebekah S
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Children's Hospital Boston
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