In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 7 ( 2021-7), p. 1682-1695
Abstract:
Whole-genome sequencing of 320 individuals with nephrotic syndrome (NS) of unclear genetic etiology and data from several independent patient cohorts provided insight into the genetic architecture of the condition. The strategy identified a disease-causing autosomal dominant mutation in regulator of calcineurin type 1 ( RCAN1 ) that increased cellular calcineurin (CN) activity, NFAT (NF of activated T cells) activation, and susceptibility to apoptosis of podocytes in vitro . Inhibition of an RCAN regulator, GSK-3 β , rescued the increased CN activation. Mutations in RCAN1 are a novel cause of NS and reveal a potential target for developing personalized therapy. Background Podocyte 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. Methods Whole-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. Results Two 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-3 β , resulting in dysregulated calcineurin activity and apoptosis. Conclusions These 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-3 β , in the treatment of FSGS.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2020081234
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
2029124-3
