mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy

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. We performed whole-exome and -genome sequencing of a...

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Published in:Journal of the American Society of Nephrology 2021-11, Vol.32 (11), p.2885-2899
Main Authors: Schlingmann, Karl P, Jouret, 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
Format: Article
Language:English
Subjects:
Cardiomyopathy, Dilated - genetics
Cardiomyopathy, Dilated - metabolism
Clinical Research
Exome Sequencing
Female
HEK293 Cells
Human health sciences
Humans
Hypercalciuria - genetics
Hypercalciuria - metabolism
Kidney Diseases - genetics
Kidney Diseases - metabolism
Kidney Tubules, Distal - metabolism
Male
Models, Molecular
Monomeric GTP-Binding Proteins - genetics
Mutation, Missense
Natriuresis - genetics
Nephrocalcinosis - genetics
Nephrocalcinosis - metabolism
Pedigree
Protein Conformation
Renal Tubular Transport, Inborn Errors - genetics
Renal Tubular Transport, Inborn Errors - metabolism
Sciences de la santé humaine
Seizures - genetics
Seizures - metabolism
Signal Transduction
TOR Serine-Threonine Kinases - metabolism
Urologie & néphrologie
Urology & nephrology
Whole Genome Sequencing
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Summary: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. 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 functional analyses of identified variants of , a gene that encodes a small Rag guanosine triphosphatase (GTPase). In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in that mostly occurred . Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by , 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 variants were shown to induce a constitutive activation of mTOR signaling . 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 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.
ISSN:1046-6673
1533-3450
1533-3450
DOI:10.1681/ASN.2021030333