Abstract
BackgroundPodocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified.MethodsWhole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes.ResultsTwo variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3β, resulting in dysregulated calcineurin activity and apoptosis.ConclusionsThese data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3β, in the treatment of FSGS.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases
Doris Duke Charitable Foundation
Borden Scholars Award
Duke Health Scholars Award
Kidney Research UK
Canadian Institutes of Health Research
McLaughlin Accelerator Award
NephCure Kidney International–NEPTUNE
Physicians Services Incorporated
Can-SOLVE CKD Network
Toronto General Hospital Foundation
National Institutes of Health
Office of Rare Diseases Research
National Center for Advancing Translational Sciences
University of Michigan
NephCure Kidney International
Halpin Foundation
Publisher
American Society of Nephrology (ASN)
Subject
Nephrology,General Medicine
Cited by
3 articles.
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