Novel genetics, pathobiology, and therapy of nephronophthisis-related ciliopathies (NPHP-RC). Nephronophthisis-related ciliopathies (NPHP-RC) are recessive cystic kidney diseases that represent the most frequent genetic cause of chronic kidney disease (CKD) in the first 30 years of life. They can be associated with retinal degeneration, liver fibrosis, and malformations of brain, bone, and other organs. Using genetic mapping and whole exome sequencing, we identified 31 of the ~80 genes that are currently known to cause NPHP-RC if mutated. Gene identification lead to the following insights: i) the ciliopathy theory of cystic kidney diseases; ii) discovery that the pathogenesis of NPHP-RC involves non-canonical Wnt signaling, planar cell polarity mechanisms, sonic hedgehog signaling and mechanisms of cell cycle regulation; iii) generation of mouse and zebrafish models of NPHP-RC; iv) the realization that in NPHP-RC developmental disorders are primarily be caused by null mutations whereas degenerative disorders are preferentially caused by hypomorphic mutations in the same NPHP-RC genes. No treatment exists for NPHP-RC. Recently, by identifying mutations in CEP164, ZNF423 and FAN1 as causing NPHP-RC, we implicated for the first time DNA damage response (DDR) signaling in the pathogenesis of ciliopathies. We also showed that with the increasing number of NPHP-RC genes identified, the encoded proteins have started to coalesce to functional NPHP-RC protein sub-complexes. We then developed a high-throughput sequencing systems that allows rapid mutation analysis on all 80 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 disease-causing genes must exist. We refined whole exome sequencing (WES) to permit identification of known or novel causative genes in >70% of WES attempts. To discover the missing ciliopathy genes, delineate the associated signaling mechanisms, and generate animal models to develop therapeutic options, we now propose to: 1. Identify and functionally characterize the missing molecular components of NPHP-related ciliopathies by whole exome sequencing in >900 families with NPHP-RC. 2. Characterize disease mechanisms for the newly identified NPHP-RC genes DCDC2 and MAPKBP1 and their relation to JNK signaling. 3. Utilize zebrafish models for allele validation, to delineate pathogenic pathways, and develop first treatment options for ciliopathies.

Public Health Relevance

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 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. To discover new NPHP-RC genes and delineate the associated signaling mechanisms, and to generate animal models to develop therapeutic options, we propose to: 1. Identify and functionally characterize the missing molecular components of NPHP-related ciliopathies by whole exome sequencing in >900 families with NPHP-RC. 2. Characterize disease mechanisms for the newly identified NPHP-RC genes DCDC2 and MAPKBP1 and their relation to JNK signaling. 3. Utilize zebrafish models for allele validation, to delineate pathogenic pathways, and develop first treatment options for ciliopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068306-13
Application #
9205225
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Rasooly, Rebekah S
Project Start
2004-06-01
Project End
2018-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
13
Fiscal Year
2017
Total Cost
$358,425
Indirect Cost
$155,925
Name
Boston Children's Hospital
Department
Type
Independent Hospitals
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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