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

1- UNIVERSITY CHILDRENS HOSPITAL MÜNSTER
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
 
Introduction:

 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. 

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 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. 

Conclusions:

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.