Discover and functionally characterize full-penetrance causes of nephrosis/FSGS. Chronic kidney diseases (CKD) take one of the highest tolls on human health, and their prevalence has been rising in the last 20 years. Nephrotic syndrome (NS) is defined by significant proteinuria, resulting in hypoalbuminemia and edema. It constitutes the second most frequent cause of CKD in children and young adults and is classified by response to a standardized steroid therapy as """"""""steroid-sensitive"""""""" (SSNS) vs. """"""""steroid-resistant"""""""" (SRNS). SRNS, with the renal histology of focal segmental glomerulosclerosis (FSGS), inevitably leads to CKD. FSGS carries a 33% risk of relapsing in a kidney transplant, causing recurrence of CKD. Since the pathogenesis of SRNS is unknown, no curative treatment is available. For SRNS, the primary causes (etiology) and disease mechanisms (pathogenesis) have been a conundrum for decades. However, gene identification of full-penetrance single-gene causes of NS (e.g. podocin) has identified the renal glomerular podocyte as the cell type at which disease mechanisms of SRNS converge. Within the previous funding period we defined genotype-phenotype correlations that allow for prognostic classification of SRNS variants. More importantly, by discovering mutations in the genes PLCE1 and COQ6, we identified by genetic mapping novel rare single-gene causes of NS that may be amenable to specific treatment. We now established a new approach of whole exome capture (WEC) and NextGen resequencing, combining it with prior homozygosity mapping (HM) to mitigate the weaknesses of the otherwise powerful WEC approach. We mapped recessive NS candidate loci in a worldwide cohort of 67 sibling cases with SRNS/SSNS. In this cohort, very recently, we identified by HM, WEC and MPS mutation of CUBN and ARHGDIA as novel single-gene causes of SRNS, and mutation of EMP2 as the first recognized cause of SSNS. We also established disease models in zebrafish and mice (for Coq6), which we will use for therapeutic studies on single-gene causes of SRNS. We, therefore will pursue the following specific aims (SAs): SA1. Discover novel single-gene causes of nephrosis by whole exome capture (WEC) and NextGen resequencing in >67 sib pairs with existing homozygosity mapping (HM) data. SA 2. Functionally characterize newly identified single-gene causes of SRNS/SSNS to delineate the pathogenesis. SA 3. For newly identified SRNS/SSNS genes study the gene function and therapeutic approaches in zebrafish and mouse models, including Coq6-/-.

Public Health Relevance

Chronic kidney diseases take one of the highest tolls on human health. Steroid-resistant nephrotic syndrome (SRNS) is a rare disease that constitutes the second most frequent cause of ESKD in children and young adults. No curative treatment is available. 25% of all SRNS cases are caused by recessive NPHS2/podocin mutations, and we recently demonstrated, by genetic mapping, that many additional single-gene causes of SRNS must exist. Identification of rare single-gene causes for SRNS has provided fundamental insights into disease mechanisms of nephrotic syndrome in children and adults. Recently, we introduced a new technology into gene discovery of rare recessive single-gene causes by developing a combined approach of homozygosity mapping with consecutive exon capture and large-scale sequencing. We have ascertained DNA samples and clinical data from over 2,600 families with SRNS world- wide and have clarified the molecular cause of SRNS in 15% of cases. We here propose to: 1) Discover novel single-gene causes of nephrosis by whole exome capture (WEC) and NextGen sequencing in >67 sib pairs with existing homozygosity mapping (HM) data;2) Functionally characterize the pathogenesis of newly identified single-gene causes of SRNS/SSNS;and 3) Study gene function and therapeutic approaches in zebrafish and mouse models for newly identified nephrosis genes including the Coq6-/- model that we have generated.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Rasooly, Rebekah S
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Children's Hospital Boston
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van der Ven, Amelie T; Connaughton, Dervla M; Ityel, Hadas et al. (2018) Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract. J Am Soc Nephrol 29:2348-2361
Daga, Ankana; Majmundar, Amar J; Braun, Daniela A et al. (2018) Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int 93:204-213
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Braun, Daniela A; Shril, Shirlee; Sinha, Aditi et al. (2018) Mutations in WDR4 as a new cause of Galloway-Mowat syndrome. Am J Med Genet A 176:2460-2465
Ashraf, Shazia; Kudo, Hiroki; Rao, Jia et al. (2018) Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat Commun 9:1960
Hermle, Tobias; Schneider, Ronen; Schapiro, David et al. (2018) GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome. J Am Soc Nephrol 29:2123-2138
Braun, Daniela A; Warejko, Jillian K; Ashraf, Shazia et al. (2018) Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome. Nephrol Dial Transplant :
Warejko, Jillian K; Tan, Weizhen; Daga, Ankana et al. (2018) Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome. Clin J Am Soc Nephrol 13:53-62
Tan, Weizhen; Lovric, Svjetlana; Ashraf, Shazia et al. (2018) Analysis of 24 genes reveals a monogenic cause in 11.1% of cases with steroid-resistant nephrotic syndrome at a single center. Pediatr Nephrol 33:305-314
Lovric, Svjetlana; Goncalves, Sara; Gee, Heon Yung et al. (2017) Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest 127:912-928

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