{"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":1789413209536,"version":"build-2803163510"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["NWO VENI 016.186.012"],"award-info":[{"award-number":["NWO VENI 016.186.012"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003092","name":"Diabetes Fonds","doi-asserted-by":"publisher","award":["2017.81.014"],"award-info":[{"award-number":["2017.81.014"]}],"id":[{"id":"10.13039\/501100003092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002997","name":"Nierstichting","doi-asserted-by":"publisher","award":["15OKG18"],"award-info":[{"award-number":["15OKG18"]}],"id":[{"id":"10.13039\/501100002997","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011102","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["FP7\/2007-2013"],"award-info":[{"award-number":["FP7\/2007-2013"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011102","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["305608"],"award-info":[{"award-number":["305608"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Fonds National de la Recherche Scientifique","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      Although advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling, some patients with tubulopathy lack a genetic diagnosis. In a cohort of patients with profound hypomagnesemia, renal salt wasting, nephrocalcinosis, and dilated cardiomyopathy, the authors performed whole-exome and -genome sequencing and identified heterozygous variants in\n                      <jats:italic toggle=\"yes\">RRAGD,<\/jats:italic>\n                      which encodes a small Rag guanosine triphosphatase (GTPase). Subsequent functional analyses\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      showed that the identified variants induce a constitutive activation of mechanistic target of rapamycin (mTOR) signaling\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . These findings not only establish a novel monogenic disorder of the kidney tubule, but demonstrate the essential role of mTOR signaling for distal tubular electrolyte handling and cardiac function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      functional analyses of identified variants of\n                      <jats:italic toggle=\"yes\">RRAGD<\/jats:italic>\n                      , a gene that encodes a small Rag guanosine triphosphatase (GTPase).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in\n                      <jats:italic toggle=\"yes\">RRAGD<\/jats:italic>\n                      that mostly occurred\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      . Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in\n                      <jats:italic toggle=\"yes\">RRAGD<\/jats:italic>\n                      that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by\n                      <jats:italic toggle=\"yes\">RRAGD<\/jats:italic>\n                      , plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified\n                      <jats:italic toggle=\"yes\">RRAGD<\/jats:italic>\n                      variants were shown to induce a constitutive activation of mTOR signaling\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the\n                      <jats:italic toggle=\"yes\">RRAGD<\/jats:italic>\n                      gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2021030333","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T16:56:03Z","timestamp":1633366563000},"page":"2885-2899","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":58,"title":["mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy"],"prefix":"10.1681","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7245-6301","authenticated-orcid":false,"given":"Karl P.","family":"Schlingmann","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, University Children\u2019s Hospital, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2547-6593","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Jouret","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Li\u00e8ge Hospital, Li\u00e8ge, Belgium"},{"name":"Interdisciplinary Group of Applied Genoproteomics, Cardiovascular Sciences, University of Li\u00e8ge, Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuang","family":"Shen","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, Massachusetts"},{"name":"Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts"},{"name":"Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts"},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts"},{"name":"Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anukrati","family":"Nigam","sequence":"additional","affiliation":[{"name":"Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Arjona","sequence":"additional","affiliation":[{"name":"Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Dafinger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Center for Molecular Medicine Cologne, Faculty of Medicine, University of Cologne and 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