mTOR-Activating Mutations in Are Causative for Kidney Tubulopathy and Cardiomyopathy
Authors
Schlingmann, Karl PJouret, François
Shen, Kuang
Nigam, Anukrati
Arjona, Francisco J
Dafinger, Claudia
Houillier, Pascal
Jones, Deborah P
Kleinerüschkamp, Felix
Oh, Jun
Godefroid, Nathalie
Eltan, Mehmet
Güran, Tülay
Burtey, Stéphane
Parotte, Marie-Christine
König, Jens
Braun, Alina
Bos, Caro
Ibars Serra, Maria
Rehmann, Holger
Zwartkruis, Fried J T
Renkema, Kirsten Y
Klingel, Karin
Schulze-Bahr, Eric
Schermer, Bernhard
Bergmann, Carsten
Altmüller, Janine
Thiele, Holger
Beck, Bodo B
Dahan, Karin
Sabatini, David
Liebau, Max C
Vargas-Poussou, Rosa
Knoers, Nine V A M
Konrad, Martin
de Baaij, Jeroen H F
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2021-10-04Keywords
Bartter syndromeTRPM6
genetic renal disease
hypokalemia
hypomagnesemia
kidney stones
mTOR
magnesium
nephrocalcinosis
rag complex
salt wasting
Metadata
Show full item recordAbstract
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 patients with tubulopathy lack a genetic diagnosis. Methods: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses 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.Source
Schlingmann KP, Jouret F, Shen K, Nigam A, Arjona FJ, Dafinger C, Houillier P, Jones DP, Kleinerüschkamp F, Oh J, Godefroid N, Eltan M, Güran T, Burtey S, Parotte MC, König J, Braun A, Bos C, Ibars Serra M, Rehmann H, Zwartkruis FJT, Renkema KY, Klingel K, Schulze-Bahr E, Schermer B, Bergmann C, Altmüller J, Thiele H, Beck BB, Dahan K, Sabatini D, Liebau MC, Vargas-Poussou R, Knoers NVAM, Konrad M, de Baaij JHF. mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy. J Am Soc Nephrol. 2021 Nov;32(11):2885-2899. doi: 10.1681/ASN.2021030333. Epub 2021 Oct 4. PMID: 34607910; PMCID: PMC8806087.DOI
10.1681/ASN.2021030333Permanent Link to this Item
http://hdl.handle.net/20.500.14038/51849PubMed ID
34607910Related Resources
This article is based on a previously available preprint in bioRxiv, https://doi.org/10.1101/2021.03.11.434334.Rights
Copyright © 2021 by the American Society of Nephrology.ae974a485f413a2113503eed53cd6c53
10.1681/ASN.2021030333