A Rare Autosomal Dominant Variant in Regulator of Calcineurin Type 1 (RCAN1) Gene Confers Enhanced Calcineurin Activity and May Cause FSGS.

Journal Article (Journal Article)

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-3β, 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-3β, in the treatment of FSGS.

Full Text

Duke Authors

Cited Authors

  • Lane, BM; Murray, S; Benson, K; Bierzynska, A; Chryst-Stangl, M; Wang, L; Wu, G; Cavalleri, G; Doyle, B; Fennelly, N; Dorman, A; Conlon, S; Vega-Warner, V; Fermin, D; Vijayan, P; Qureshi, MA; Shril, S; Barua, M; Hildebrandt, F; Pollak, M; Howell, D; Sampson, MG; Saleem, M; Conlon, PJ; Spurney, R; Gbadegesin, R

Published Date

  • April 16, 2021

Published In

PubMed ID

  • 33863784

Electronic International Standard Serial Number (EISSN)

  • 1533-3450

Digital Object Identifier (DOI)

  • 10.1681/ASN.2020081234

Language

  • eng

Conference Location

  • United States