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mTOR-activating mutations in RRAGD are causative for kidney tubulopathy and cardiomyopathy

Item Type:Article
Title:mTOR-activating mutations in RRAGD are causative for kidney tubulopathy and cardiomyopathy
Creators Name:Schlingmann, K.P. and Jouret, F. and Shen, K. and Nigam, A. and Arjona, F. and Dafinger, C. and Houillier, P. and Jones, D. and Kleinerüschkamp, F. and Oh, J. and Godefroid, N. and Eltan, M. and Güran, T. and Burtey, S. and Parotte, M.C. and König, J. and Braun, A. and Bos, C. and Serra, M.I. and Rehmann, H. and Zwartkruis, F. and Renkema, K. and Klingel, K. and Schulze-Bahr, E. and Schermer, B. and Bergmann, C. and Altmüller, J. and Thiele, H. and Beck, B. and Dahan, K. and Sabatini, D. and Liebau, M. and Vargas-Poussou, R. and Knoers, N. and Konrad, M. and de Baaij, J.
Abstract:BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all tubulopathy patients lack a genetic diagnosis. METHODS: We performed whole-exome and genome sequencings of a patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia, and dilated cardiomyopathy. We also conducted subsequent functional analyses in vitro of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight 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 also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD encoded by RRAGD plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included 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. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
Keywords:Hypomagnesemia, Bartter Syndrome, Genetic Renal Disease, Magnesium, Kidney Stones, TRPM6, Nephrocalcinosis, Hypokalemia, mTOR, Rag Complex, Salt Wasting
Source:Journal of the American Society of Nephrology
ISSN:1046-6673
Publisher:American Society of Nephrology
Volume:32
Number:11
Page Range:2885-2899
Date:29 October 2021
Official Publication:https://doi.org/10.1681/ASN.2021030333
PubMed:View item in PubMed

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