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The strategy identified a disease-causing autosomal dominant mutation in regulator of calcineurin type 1 (\n                      <jats:italic toggle=\"yes\">RCAN1<\/jats:italic>\n                      ) that increased cellular calcineurin (CN) activity, NFAT (NF of activated T cells) activation, and susceptibility to apoptosis of podocytes\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . Inhibition of an RCAN regulator, GSK-3\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      , rescued the increased CN activation. Mutations in\n                      <jats:italic toggle=\"yes\">RCAN1<\/jats:italic>\n                      are a novel cause of NS and reveal a potential target for developing personalized therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two variants in the gene encoding regulator of calcineurin type 1 (\n                      <jats:italic toggle=\"yes\">RCAN1<\/jats:italic>\n                      ) segregate with disease in two families with autosomal dominant FSGS\/SRNS.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      , loss of\n                      <jats:italic toggle=\"yes\">RCAN1<\/jats:italic>\n                      reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant\n                      <jats:italic toggle=\"yes\">RCAN1<\/jats:italic>\n                      displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type\n                      <jats:italic toggle=\"yes\">RCAN1<\/jats:italic>\n                      . Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      , resulting in dysregulated calcineurin activity and apoptosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These data suggest mutations in\n                      <jats:italic toggle=\"yes\">RCAN1<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      , in the treatment of FSGS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2020081234","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T11:10:45Z","timestamp":1618571445000},"page":"1682-1695","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":6,"title":["A Rare Autosomal Dominant Variant in Regulator of Calcineurin Type 1 (RCAN1) Gene Confers Enhanced Calcineurin Activity and May Cause FSGS"],"prefix":"10.1681","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1158-1117","authenticated-orcid":false,"given":"Brandon M.","family":"Lane","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Pediatrics, Duke 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