Focal segmental glomerulosclerosis (FSGS) is a frequent cause of end-stage renal disease. The pathogenesis of FSGS has not been precisely defined and there are no consistently effective treatments. Recent studies identifying causal genes in rare, inherited FSGS, including our own study, have associated mutations in at least six genes with familial FSGS, and each discovery has clarified molecular mechanisms of glomerular injury. To build on this productive line of inquiry, we have ascertained and carefully characterized 118 families with familial FSGS. We have screened the remainder of our families for mutations in genes known to cause FSGS and identified the causal mutations in an additional 6 kindreds;the genetic basis of disease in the remaining 111 families is unknown. The objective of this proposal is to use this valuable and unique family resource to systematically identify causal genes for familial FSGS. Limitations of current conventional linkage and positional cloning approaches include their requirement for large, multiplex families. In addition, narrowing candidate areas in traditional linkage analysis can be difficult due to larg regions that lack recombination events and hence these regions have required cumbersome and lengthy screening for causative mutations. Powerful new genetic tools can facilitate this screening process and improve variant discovery in smaller families. In particular, efficient whole-exome sequencing, the targeted capture of protein-coding gene sequences, should be particularly useful in our studies since most Mendelian disorders are caused by mutations affecting exomes of the target gene. Thus, by combining genome-wide linkage analysis (GWLS) and whole-exome sequencing, we can maximize impact of our family data and accelerate identification of novel mutations in FSGS. In preliminary studies, we have used this combination to identify a novel variant in the WT1 (Wilms'Tumor-1) gene in one FSGS family, and we have evidence suggesting it is the causal mutation. This success provides proof-of-concept and provides a roadmap of how genes will be identified and evaluated in the proposed studies. Our hypothesis is that causes of inherited FSGS in our cohort of families will be sequence variants in the coding region of genes not previously associated with familial FSGS.
We aim to: 1) Use GWLS and whole-exome sequencing to identify genetic variants associated with familial FSGS. 2) Characterize functional consequences of candidate causative mutations and 3) Determine the prevalence in the Duke FSGS dataset of these new causative mutations identified in Aim 2. Any genes found to have causative mutations will be sequenced in the remaining families and take full advantage of our family resource. By combining genome-wide linkage analysis (GWLS), whole-exome sequencing, and characterization of variants'functional consequences, we will significantly improve understanding of normal glomerular biology and of the pathogenesis of FSGS and related glomerular diseases. Moreover, our discoveries are likely to reveal new opportunities to improve therapy for a disease that currently has few effective treatments.

Public Health Relevance

This grant analyzes 20 families with autosomal dominant, hereditary focal segmental glomerulosclerosis (FSGS). The linkage analysis will be performed and the human exome will be sequenced in each of these families to help understand the genetic basis for their kidney disease, better understand the underlying pathogenesis and to hopefully find better treatment options for those with FSGS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094987-03
Application #
8708853
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Rasooly, Rebekah S
Project Start
2012-09-18
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$429,265
Indirect Cost
$155,848
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Hall, Gentzon; Gbadegesin, Rasheed A (2015) Translating genetic findings in hereditary nephrotic syndrome: the missing loops. Am J Physiol Renal Physiol 309:F24-8
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Rheault, Michelle N; Zhang, Lei; Selewski, David T et al. (2015) AKI in Children Hospitalized with Nephrotic Syndrome. Clin J Am Soc Nephrol 10:2110-8
Phelan, Paul J; Hall, Gentzon; Wigfall, Delbert et al. (2015) Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation. Clin Kidney J 8:538-42
Gbadegesin, Rasheed A (2015) The author replies. Kidney Int 87:859-60
Hall, Gentzon; Gbadegesin, Rasheed A; Lavin, Peter et al. (2015) A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS. J Am Soc Nephrol 26:831-43
Malone, Andrew F; Phelan, Paul J; Hall, Gentzon et al. (2014) Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int 86:1253-9
Hall, Gentzon; Rowell, Janelle; Farinelli, Federica et al. (2014) Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity. Am J Physiol Renal Physiol 306:F1442-50

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