ESPN 54th Annual Meeting

ESPN 2022

mTOR-activating mutations in RRAGD cause kidney tubulopathy and cardiomyopathy syndrome
SCHLINGMANN KARL 1 Jouret Francois 2 Shen Kuang 3 Dafinger Claudia 4 Houillier Pascal 5 Oh Jun 6 Godefroid Nathalie 7 Schermer Bernhard 8 Bergmann Carsten 9 Beck Bodo 10 Sabatini David 1 Liebau Max 4 Vargas-Poussou Rosa 11 Knoers Nine 12 de Baaij Jeroen 13 Konrad Martin 1

2- Department of Internal Medicine, University of Liège, Belgium
3- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
4- Department of Pediatrics, University Hospital Cologne, Germany
5- Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France
6- Department of Pediatrics, University Medical Center Hamburg, Germany
7- Division of Pediatric Nephrology, UC Louvain, Brussels, Belgium
8- Department II of Internal Medicine, University Hospital Cologne, Germany
9- Departmen of Medicine, Division of Nephrology, University Hospital Freiburg, Germany
10- Department of Human Genetics, University Hospital Cologne, Germany
11- Department of Genetics, Hôpital Européen Georges-Pompidou, Paris, France
12- Department of Genetics, University Medical Center Groningen
13- Department of Physiology, Radboud university medical center Nijmegen, The Netherlands

 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).

Material and methods:

 Whole exome and genome sequencing was performed with 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 requiring heart transplantation in 3 of them. An additional 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). Identified RRAGD variants were shown to induce an increased interaction with components of mTORC1 and a constitutive activation of mTOR signaling in vitro. 


Our findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.