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Kidney Week

Abstract: TH-OR21

mTOR-Activating Mutations in RRAGD Cause Kidney Tubulopathy and Cardiomyopathy (KICA) Syndrome

Session Information

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.