Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives

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 ta...

Descripción completa

Detalles Bibliográficos
Autores: Madariaga, Leire|||0000-0002-4032-9842, Ariceta Iraola, Gema|||0000-0003-1763-1098, Bockenhauer, Detlef, De Frutos, Fernando|||0000-0003-4350-3217, Möller, Thomas|||0000-0002-1159-3206, Adella, Anastasia, Jouret, François, Leermakers, Pieter A., Arango, Pedro, Beck, Bodo B., Bjerre, Anna, Coccia, Paula, Dhamija, Radhika, Garcia-Castaño, Alejandro, van Katwijk, Sara B., Lucas, Jesus, Müller, Dominik, Pinto e Vairo, Filippo, Raki, Melinda, Rips, Jonathan, Schlingmann, Karl Peter, Venselaar, Hanka, Machado Bressan Wilke, Matheus Vernet, Nijenhuis, Tom, Hoenderop, Joost, de Baaij, Jeroen
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:dnet:uabarcelona_::ed533bd3da904af198a5092da9c0840c
Acceso en línea:https://ddd.uab.cat/record/328077
https://dx.doi.org/urn:doi:10.1016/j.ekir.2025.07.035
Access Level:acceso abierto
Palabra clave:Dapagliflozin
Dilated cardiomyopathy
Kidney tubulopathy
Magnesium
mTORC1
RRAGD
Descripción
Sumario: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. 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. 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 (Mg 2+) levels by 0.04 mM but exacerbated hypokalemia. 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 Mg 2+ levels in patients with RRAGD variants.

Similares en LA Referencia