mTOR-activating mutations of RRAGD cause a novel syndrome combining kidney tubulopathy and cardiomyopathy

Introduction Advances in genetic techniques have resulted in the identification of rare inherited disorders of renal magnesium and salt handling. Nevertheless, ∼20% of all patients with primary kidney tubulopathy have no diagnosis. Description We explore a large multicentric cohort presenting with a novel inherited salt-losing tubulopathy mostly characterized by hypomagnesemia, combined with early-onset dilated cardiomyopathy (DCM). Methods Whole exome and genome sequencings 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 before the age of 25y. A dominant variant in RRAGD was simultaneously identified in 8 members of a large family, which segregated with a similar renal magnesium-losing phenotype. No DCM was detected in this family. RRAGD encodes Rag GTPase D mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron includes 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 diseased 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.