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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| 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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oai:recercat.cat:2445/224341 |
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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 Diürètics Osteodistròfia renal Glomèruls renals Diuretics Renal osteodystrophy Kidney glomerulus 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/). Elsevier BV https://hdl.handle.net/2445/224341 |
| 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 |
| 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 |
| topic |
Diürètics Osteodistròfia renal Glomèruls renals Diuretics Renal osteodystrophy Kidney glomerulus |
| topic_facet |
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/). |
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2025 |
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https://hdl.handle.net/2445/224341 |
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openAccess |
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Elsevier BV |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| collection |
Recercat. Dipósit de la Recerca de Catalunya |
| reponame_str |
Recercat. Dipósit de la Recerca de Catalunya |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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1878435091718340609 |
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2025 |
| author_browse |
Adella, Anastasia Arango, Pedro Ariceta, Gema Baaij, Jeroen de Beck, Bodo B. Bjerre, Anna Bockenhauer, Detlef Coccia, Paula Dhamija, Radhika Frutos, Fernando de Garcia Castano, Alejandro Hoenderop, Joost Jouret, François Leermakers, Pieter A. Lucas, Jesús Madariaga, Leire Möller, Thomas Müller, Dominik Nijenhuis, Tom Peter Schlingmann, Karl Pinto e Vairo, Filippo Raki, Melinda Rips, Jonathan Van Katwijk, Sara B. Venselaar, Hanka Vernet Machado Bressan Wilke, Matheus |
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Elsevier BV |
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6.924472 |