Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives

Adella, Anastasia; Jouret, François; Madariaga, Leire; Leermakers, Pieter A.; Arango, Pedro; Ariceta, Gema; Beck, Bodo B.; Bjerre, Anna; Bockenhauer, Detlef; Coccia, Paula; Dhamija, Radhika; Frutos, Fernando de; Garcia Castano, Alejandro; Van Katwijk, Sara B.; Lucas, Jesús; Möller, Thomas; Müller, Dominik; Pinto e Vairo, Filippo; Raki, Melinda; Rips, Jonathan; Peter Schlingmann, Karl; Venselaar, Hanka; Vernet Machado Bressan Wilke, Matheus; Nijenhuis, Tom; Hoenderop, Joost; Baaij, Jeroen de

Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives

Introduction: Variants in the Ras-related GTPase D (RRAGD) gene have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy (DCM). RRAGD, which encodes for the RagD protein, is involved in the activation of the...

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Autores:	Adella, Anastasia, Jouret, François, Madariaga, Leire, Leermakers, Pieter A., Arango, Pedro, Ariceta, Gema, Beck, Bodo B., Bjerre, Anna, Bockenhauer, Detlef, Coccia, Paula, Dhamija, Radhika, Frutos, Fernando de, Garcia Castano, Alejandro, Van Katwijk, Sara B., Lucas, Jesús, Möller, Thomas, Müller, Dominik, Pinto e Vairo, Filippo, Raki, Melinda, Rips, Jonathan, Peter Schlingmann, Karl, Venselaar, Hanka, Vernet Machado Bressan Wilke, Matheus, Nijenhuis, Tom, Hoenderop, Joost, Baaij, Jeroen de
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2025
País:	España
Institución:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:2445/224341
Acceso en línea:	https://hdl.handle.net/2445/224341
Access Level:	acceso abierto
Palabra clave:	Diürètics Osteodistròfia renal Glomèruls renals Diuretics Renal osteodystrophy Kidney glomerulus

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spelling	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic PerspectivesAdella, AnastasiaJouret, FrançoisMadariaga, LeireLeermakers, Pieter A.Arango, PedroAriceta, GemaBeck, Bodo B.Bjerre, AnnaBockenhauer, DetlefCoccia, PaulaDhamija, RadhikaFrutos, Fernando deGarcia Castano, AlejandroVan Katwijk, Sara B.Lucas, JesúsMöller, ThomasMüller, DominikPinto e Vairo, FilippoRaki, MelindaRips, JonathanPeter Schlingmann, KarlVenselaar, HankaVernet Machado Bressan Wilke, MatheusNijenhuis, TomHoenderop, JoostBaaij, Jeroen deDiürèticsOsteodistròfia renalGlomèruls renalsDiureticsRenal osteodystrophyKidney glomerulusIntroduction: Variants in the Ras-related GTPase D (RRAGD) gene have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy (DCM). RRAGD, which encodes for the RagD protein, is involved in the activation of the mechanistic target of rapamycin complex 1 (mTORC1). Owing to the limited characterization of patients' phenotypes, the understanding of RRAGD-associated ADKH (ADKH-RRAGD) remains incomplete. Consequently, available treatment strategies are primarily symptomatic and insufficient. Methods: In the present case series, 13 new patients and 3 novel RRAGD variants, that is, p.(Ser77Phe), p. (Thr91Ile), and p.(Ile100Arg), are described. To assess the pathogenicity of the novel variants, an in vitro assay of mTORC1 activity was performed. In addition, the clinical response to diuretics (furosemide and thiazide, n = 4) and Na+-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (n = 6) was evaluated in patients carrying the RRAGD p.(Thr97Pro) variant during routine. Results: The patients presented with kidney tubulopathies, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Five patients also exhibited DCM. In vitro assays demonstrated constitutive activation of noncanonical mTORC1 signaling caused by the p.(Ser77Phe) and p.(Ile100Arg) variants. Clinically, patients remained sensitive to diuretic challenges, whereas dapagliflozin treatment increased serum magnesium (Mg2+) levels by 0.04 mM but exacerbated hypokalemia. Conclusion: To date, 37 patients with ADKH-RRAGD have been identified. Kidney tubulopathy is the most prominent feature within the phenotypic spectrum of ADKH-RRAGD. Molecularly, constitutive activation of noncanonical mTORC1 is present in most RRAGD variants. From a therapeutic perspective, dapagliflozin may increase serum Mg2+ levels in patients with RRAGD variants. (c) 2025 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Elsevier BV2025202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/224341Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.ekir.2025.07.035Kidney International Reports, 2025, vol. 10, num. 10, 3640-3655https://doi.org/10.1016/j.ekir.2025.07.035cc-by (c) International Society of Nephrology, 2025https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2243412026-05-29T05:05:01Z
dc.title.none.fl_str_mv	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
title	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
spellingShingle	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives Adella, Anastasia Diürètics Osteodistròfia renal Glomèruls renals Diuretics Renal osteodystrophy Kidney glomerulus
title_short	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
title_full	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
title_fullStr	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
title_full_unstemmed	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
title_sort	Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives
dc.creator.none.fl_str_mv	Adella, Anastasia Jouret, François Madariaga, Leire Leermakers, Pieter A. Arango, Pedro Ariceta, Gema Beck, Bodo B. Bjerre, Anna Bockenhauer, Detlef Coccia, Paula Dhamija, Radhika Frutos, Fernando de Garcia Castano, Alejandro Van Katwijk, Sara B. Lucas, Jesús Möller, Thomas Müller, Dominik Pinto e Vairo, Filippo Raki, Melinda Rips, Jonathan Peter Schlingmann, Karl Venselaar, Hanka Vernet Machado Bressan Wilke, Matheus Nijenhuis, Tom Hoenderop, Joost Baaij, Jeroen de
author	Adella, Anastasia
author_facet	Adella, Anastasia Jouret, François Madariaga, Leire Leermakers, Pieter A. Arango, Pedro Ariceta, Gema Beck, Bodo B. Bjerre, Anna Bockenhauer, Detlef Coccia, Paula Dhamija, Radhika Frutos, Fernando de Garcia Castano, Alejandro Van Katwijk, Sara B. Lucas, Jesús Möller, Thomas Müller, Dominik Pinto e Vairo, Filippo Raki, Melinda Rips, Jonathan Peter Schlingmann, Karl Venselaar, Hanka Vernet Machado Bressan Wilke, Matheus Nijenhuis, Tom Hoenderop, Joost Baaij, Jeroen de
author_role	author
author2	Jouret, François Madariaga, Leire Leermakers, Pieter A. Arango, Pedro Ariceta, Gema Beck, Bodo B. Bjerre, Anna Bockenhauer, Detlef Coccia, Paula Dhamija, Radhika Frutos, Fernando de Garcia Castano, Alejandro Van Katwijk, Sara B. Lucas, Jesús Möller, Thomas Müller, Dominik Pinto e Vairo, Filippo Raki, Melinda Rips, Jonathan Peter Schlingmann, Karl Venselaar, Hanka Vernet Machado Bressan Wilke, Matheus Nijenhuis, Tom Hoenderop, Joost Baaij, Jeroen de
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Diürètics Osteodistròfia renal Glomèruls renals Diuretics Renal osteodystrophy Kidney glomerulus
topic	Diürètics Osteodistròfia renal Glomèruls renals Diuretics Renal osteodystrophy Kidney glomerulus
description	Introduction: Variants in the Ras-related GTPase D (RRAGD) gene have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy (DCM). RRAGD, which encodes for the RagD protein, is involved in the activation of the mechanistic target of rapamycin complex 1 (mTORC1). Owing to the limited characterization of patients' phenotypes, the understanding of RRAGD-associated ADKH (ADKH-RRAGD) remains incomplete. Consequently, available treatment strategies are primarily symptomatic and insufficient. Methods: In the present case series, 13 new patients and 3 novel RRAGD variants, that is, p.(Ser77Phe), p. (Thr91Ile), and p.(Ile100Arg), are described. To assess the pathogenicity of the novel variants, an in vitro assay of mTORC1 activity was performed. In addition, the clinical response to diuretics (furosemide and thiazide, n = 4) and Na+-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (n = 6) was evaluated in patients carrying the RRAGD p.(Thr97Pro) variant during routine. Results: The patients presented with kidney tubulopathies, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Five patients also exhibited DCM. In vitro assays demonstrated constitutive activation of noncanonical mTORC1 signaling caused by the p.(Ser77Phe) and p.(Ile100Arg) variants. Clinically, patients remained sensitive to diuretic challenges, whereas dapagliflozin treatment increased serum magnesium (Mg2+) levels by 0.04 mM but exacerbated hypokalemia. Conclusion: To date, 37 patients with ADKH-RRAGD have been identified. Kidney tubulopathy is the most prominent feature within the phenotypic spectrum of ADKH-RRAGD. Molecularly, constitutive activation of noncanonical mTORC1 is present in most RRAGD variants. From a therapeutic perspective, dapagliflozin may increase serum Mg2+ levels in patients with RRAGD variants. (c) 2025 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
publishDate	2025
dc.date.none.fl_str_mv	2025 2025 2025 2025
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/224341
url	https://hdl.handle.net/2445/224341
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1016/j.ekir.2025.07.035 Kidney International Reports, 2025, vol. 10, num. 10, 3640-3655 https://doi.org/10.1016/j.ekir.2025.07.035
dc.rights.none.fl_str_mv	cc-by (c) International Society of Nephrology, 2025 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	cc-by (c) International Society of Nephrology, 2025 https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Elsevier BV
publisher.none.fl_str_mv	Elsevier BV
dc.source.none.fl_str_mv	Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
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Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives

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