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

Abstract

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. 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. Two variants in the gene encoding regulator of calcineurin type 1 (<i>RCAN1</i>) segregate with disease in two families with autosomal dominant FSGS/SRNS. <i>In vitro</i>, loss of <i>RCAN1</i> reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant <i>RCAN1</i> displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type <i>RCAN1</i>. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3<i>β</i>, resulting in dysregulated calcineurin activity and apoptosis. These data suggest mutations in <i>RCAN1</i> 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<i>β</i>, in the treatment of FSGS.