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

Brandon M Lane, Susan Murray, Katherine Benson, Agnieszka Bierzynska, Megan Chryst-Stangl, Liming Wang, Guanghong Wu, Gianpiero Cavalleri, Brendan Doyle, Neil Fennelly, Anthony Dorman, Shane Conlon, Virginia Vega-Warner, Damian Fermin, Poornima Vijayan, Mohammad Azfar Qureshi, Shirlee Shril, Moumita Barua, Friedhelm Hildebrandt, Martin PollakDavid Howell, Matthew G Sampson, Moin Saleem, Peter J Conlon, Robert Spurney, Rasheed Gbadegesin

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1682-1695
Number of pages14
JournalJournal of the American Society of Nephrology
Volume32
Issue number7
Early online date16 Apr 2021
DOIs
Publication statusPublished - Jul 2021

Bibliographical note

Funding Information:
M. Barua reports having ownership interest in AstraZeneca; serving on the editorial board of Glomerular Diseases; and receiving research funding from Otsuka, Regulus, and Sanofi. K. Benson reports serving as chair of the ClinGen Kidney Cystic and Ciliopathy Disorders Variant Curation Expert Panel. R. Gbadegesin reports receiving research funding from AstraZeneca, Bristol Myers Squibb, and Goldfinch Biotech; and having consultancy agreements with Keryx Pharmaceutical. F. Hildebrandt reports having consultancy agreements with, ownership interest in, and serving as a scientific advisor for or member of Goldfinch Bio as cofounder; and receiving honoraria from Sanofi. S. Murray reports receiving research funding from Amgen. M. Pollak reports having ownership interest in Apolo1Bio; having patents and inventions with

Funding Information:
Molecular graphics and analyses of PDB files created in the I-TASSER software48,49 was performed with UCSF ChimeraX, which was developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health (NIH) (R01-GM129325) and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases.50

Funding Information:
Athena Diagnostics; serving on the NephCure Foundation scientific advisory board; having consultancy agreements with, and receiving research funding from, Vertex; and receiving honoraria from various academic talks. Because M. Pollak is an editor of the JASN, he was not involved in the peer review process for this manuscript. A guest editor oversaw the peer review and decision-making process for this manuscript. M. Saleem reports receiving research funding from Evotec, Retrophin, and UCB; having consultancy agreements with Mission Therapeutics, Pfizer, and Retrophin; having ownership interest in Purespring Therapeutics; and receiving honoraria from Purespring Therapeutics as director and chief scientific officer. M. G. Sampson reports having consultancy agreements with Janssen Pharmaceutical, Kohlberg Kravis Roberts & Co.; and serving as a scientific advisor for, or member of, Natera. R. Spurney reports serving as scientific advisor for, or member of, the American Journal of Physiology; and having consultancy agreements with Amgen and Tectonic. Additional funding and/or programmatic support for NEPTUNE has also been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation.Additional funding and/or programmatic support for NEPTUNE has also been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. All remaining authors have nothing to disclose.

Funding Information:
R. Gbadegesin is supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants 5R01DK098135 and 5R01DK094987, Doris Duke Charitable Foundation Clinical Scientist Development Award 2009033, Borden Scholars Award, and the Duke Health Scholars Award. B. M. Lane is supported by NIDDK Duke Nephrology Award, grant T32-DK007731. A. Bierzynska is funded by Kidney Research UK (personal nonclinical fellowship). M. Barua has received Canadian Institutes of Health Research grant 432980, McLaughlin Accelerator Award (2019), NephCure Kidney International–NEPTUNE Ancillary Studies Grant (2016), and Physicians Services Incorporated Health Research Grant 14-04 (2015); and support from the Can-SOLVE CKD Network (https://www.cansolveckd.ca/) and Toronto General Hospital Foundation. M.G. Sampson is supported by National Institutes of Health (NIH) grants R01-DK108805 and R01-DK119380. NEPTUNE is a part of the NIH Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and NIDDK, under grant U54-DK-083912.

Publisher Copyright:
© 2021 by the American Society of Nephrology

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