ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

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


  • 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

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).


Whole exome and genome sequencing were performed with various subsequent functional analyses of identified RRAGD variants in vitro.


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.


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.