Abstract: TH-OR21
mTOR-Activating Mutations in RRAGD Cause Kidney Tubulopathy and Cardiomyopathy (KICA) Syndrome
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic and Clinical Research
November 04, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Fluid, Electrolyte, and Acid-Base Disorders
- 902 Fluid, Electrolyte, and Acid-Base Disorders: Clinical
Authors
- De Baaij, Jeroen H.F., Radboudumc, Nijmegen, Gelderland, Netherlands
- Schlingmann, Karl P., Universitatsklinikum Munster, Munster, Nordrhein-Westfalen, Germany
- Jouret, Francois, Universite de Liege, Liege, Belgium
- Dafinger, Claudia, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany
- Houillier, Pascal, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
- Liebau, Max, University of Cologne Center for Molecular Medicine Cologne, Cologne, Nordrhein-Westfalen, Germany
- Vargas-Poussou, Rosa, Hopital Europeen Georges Pompidou, Paris, Île-de-France, France
- Knoers, Nine V., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
- Konrad, Martin, Universitatsklinikum Munster, Munster, Nordrhein-Westfalen, Germany
Background
Over the last decades, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, ±20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM).
Methods
Whole exome and genome sequencing were performed with various subsequent functional analyses of identified RRAGD variants in vitro.
Results
In 8 children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt-wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients additionally suffered from DCM and a heart transplantation was performed in 3 of them. A dominant variant in RRAGD was simultaneously identified in eight members of a large family with a similar renal phenotype. RRAGD encodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro.
Conclusion
Our findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.