{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T19:13:29Z","timestamp":1789413209117,"version":"build-2803163510"},"reference-count":58,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["OCENW.M.21.022"],"award-info":[{"award-number":["OCENW.M.21.022"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["VIDI 391 09150172110040"],"award-info":[{"award-number":["VIDI 391 09150172110040"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,6,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Autosomal dominant kidney hypomagnesemia with\n                    <jats:italic>RRAGD<\/jats:italic>\n                    variants (ADKH\u2010\n                    <jats:italic>RRAGD<\/jats:italic>\n                    ) is a hereditary disorder characterized by kidney tubulopathy and dilated cardiomyopathy (DCM). RagD, encoded by the\n                    <jats:italic>RRAGD<\/jats:italic>\n                    gene, is a small GTPase involved in activating the mechanistic target of rapamycin complex 1 (mTORC1) by amino acids. Although several gain\u2010of\u2010function variants in the\n                    <jats:italic>RRAGD<\/jats:italic>\n                    gene have been identified, their contributions to DCM remain unclear. Here, we hypothesize that these\n                    <jats:italic>RRAGD<\/jats:italic>\n                    variants induce mTORC1 overactivation, thereby contributing to the manifestation of DCM. To investigate this, we established T\u2010REx HeLa cell lines that overexpress the\n                    <jats:italic>RRAGD<\/jats:italic>\n                    p.(Ser76Leu) or the wild\u2010type (WT) variant to assess the effects on mTORC1 signaling. Additionally, we developed the first cellular model of ADKH\u2010\n                    <jats:italic>RRAGD<\/jats:italic>\n                    utilizing genetically edited human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes (hiPSC\u2010CMs) that express the mutated variant. Our data indicate that the\n                    <jats:italic>RRAGD<\/jats:italic>\n                    p.(Ser76Leu) variant maintains the phosphorylation of mTORC1 targets (i.e., S6K, 4E\u2010BP1, and TFEB) during amino acid starvation, in contrast to\n                    <jats:italic>RRAGD<\/jats:italic>\n                    WT in T\u2010REx HeLa cells. The pharmacological inhibition of mTOR with Torin1 reversed these changes. In 2D\u2010cultured\n                    <jats:italic>RRAGD<\/jats:italic>\n                    <jats:sup>WT\/p.(Ser76Leu)<\/jats:sup>\n                    hiPSC\u2010CMs, mTORC1 remained responsive to amino acid starvation. Results from bulk RNA sequencing showed an upregulation of pathways associated with cytoskeletal organization and a downregulation of muscle development in\n                    <jats:italic>RRAGD<\/jats:italic>\n                    <jats:sup>WT\/p.(Ser76Leu)<\/jats:sup>\n                    hiPSC\u2010CMs. Moreover, a prolonged duration of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients was observed in the mutant cardiomyocytes. Altogether, our data demonstrate that gain\u2010of\u2010function variants in\n                    <jats:italic>RRAGD<\/jats:italic>\n                    cause mTORC1 activation in T\u2010REx HeLa cells. Consequently, cardiomyocytes develop impaired intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    clearance and activation of transcriptional programs, suggesting dedifferentiation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501099rr","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T15:00:08Z","timestamp":1782140408000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>\n                      <i>RRAGD<\/i>\n                    <\/scp>\n                    p.(\n                    <scp>Ser76Leu<\/scp>\n                    ) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes"],"prefix":"10.1096","volume":"40","author":[{"given":"Anastasia","family":"Adella","sequence":"first","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5967-2255","authenticated-orcid":false,"given":"Sara B.","family":"van Katwijk","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0145-742X","authenticated-orcid":false,"given":"Pieter A.","family":"Leermakers","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem B.","family":"van Ham","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesther","family":"de Ruiter","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judita","family":"Ilgutyt\u0117","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Hendrickx","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi","family":"Nijland","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teun P.","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2026-9408","authenticated-orcid":false,"given":"Eva","family":"van Rooij","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht  Utrecht the Netherlands"},{"name":"Division Heart and Lungs, Department of Cardiology University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost G. J.","family":"Hoenderop","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2372-8486","authenticated-orcid":false,"given":"Jeroen H. F.","family":"de Baaij","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences Radboudumc  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2021030333"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38428-2"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2025.07.035"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.123.004336"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax3939"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0166"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1753"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1157535"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004389200"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.111.1.11"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.48.28982"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.10.024"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207542"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.11.1422"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2152"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.19653"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002790"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.32"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302022"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311147"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054221"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43008"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5241"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115494"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100838"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00705.2023"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1271514"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky354"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19441-8"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0399-6"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-024-04074-8"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-5213-9"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-13864-6_3"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.110.937805"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2022.10.010"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003552"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-025-01103-x"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0331-x"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-021-02252-6"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.044205"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2023.12.004"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164680"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.026"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103574"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1159\/000539889"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00695.2024"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.977066"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2016.04.011"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-020-01365-9"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.123.011110"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm12071149"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2020.11.016"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1535-6"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.10.001"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaccao.2024.07.012"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318183"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202501099RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202501099RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202501099RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T16:23:41Z","timestamp":1782318221000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202501099RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":58,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2026,6,30]]}},"alternative-id":["10.1096\/fj.202501099RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202501099rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]},"assertion":[{"value":"2025-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72070"}}