Identification of the first several nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) genes has had a significant impact on the understanding of glomerular function and disease. However, It is clear that the known genes account for only a fraction of these diseases. Here our goal is further elucidation of the genetic basis of FSGS, using a database of over 2500 individuals assembled over the past eleven years. Specifically, we will perform mutational analysis of known FSGS genes in families with FSGS and in patients with sporadic FSGS. We will continue our ongoing ascertainment of families with FSGS as well as sporadic adult and pediatric cases. Mutational analysis of these known FSGS genes will further inform our understanding of the spectrum of mutations, inform genotype/phenotype relationships, provide further information regarding structure and function, and help clarify the utility of genetic testing. We will also aim to Identify new FSGS genes. Through genome-wide scans, we have identified several genetic regions that appear to harbor as yet unidentified FSGS genes. We will analyze genes within these disease-associated regions in order to identify disease-associated variation. We will continue to perform additional genome-wide scans in new, genetically informative families as they are ascertained. We will test the hypothesis that rare DNA sequence variants in critical podocyte/glomerulus genes contribute to the etiology of FSGS. We will resequence candidate genes in 300 FSGS cases and 300 controls and determine if rare deleterious variants in these genes are more common in cases. We will replicate positive results in independent sample sets. FSGS is a significant and growing cause of chronic kidney disease and kidney failure. FSGS is also a common consequence of a variety of primary conditions. These studies will help understand the underlying causes of this disease.

Public Health Relevance

The identification of new focal segmental glomerulosclerosis (FSGS) genes and further genetic characterization of known FSGS genes will have significant implications for understanding, and ultimately, treating, common forms of renal failure and renal failure progression. In the more immediate future, identification and characterization of FSGS gene defects will have implications for the development of diagnostic tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054931-14
Application #
8287701
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
2010-06-01
Project End
2013-08-15
Budget Start
2012-03-01
Budget End
2013-08-15
Support Year
14
Fiscal Year
2012
Total Cost
$373,419
Indirect Cost
$157,747
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Barua, Moumita; Shieh, Eric; Schlondorff, Johannes et al. (2014) Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis. Kidney Int 85:124-33
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