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

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 () segregate with disease in two families with autosomal dominant FSGS/SRNS. , loss of reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type . Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3, resulting in dysregulated calcineurin activity and apoptosis.

CONCLUSIONS

These data suggest mutations in 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, in the treatment of FSGS.