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

Author:

Lane Brandon M.ORCID,Murray Susan,Benson Katherine,Bierzynska Agnieszka,Chryst-Stangl Megan,Wang LimingORCID,Wu Guanghong,Cavalleri GianpieroORCID,Doyle Brendan,Fennelly Neil,Dorman Anthony,Conlon Shane,Vega-Warner Virginia,Fermin DamianORCID,Vijayan PoornimaORCID,Qureshi Mohammad Azfar,Shril Shirlee,Barua Moumita,Hildebrandt Friedhelm,Pollak Martin,Howell David,Sampson Matthew G.,Saleem MoinORCID,Conlon Peter J.ORCID,Spurney Robert,Gbadegesin RasheedORCID

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

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