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

TY - JOUR

T1 - mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy

AU - Schlingmann, Karl P

AU - Jouret, François

AU - Shen, Kuang

AU - Nigam, Anukrati

AU - Arjona, Francisco J

AU - Dafinger, Claudia

AU - Houillier, Pascal

AU - Jones, Deborah P

AU - Kleinerüschkamp, Felix

AU - Oh, Jun

AU - Godefroid, Nathalie

AU - Eltan, Mehmet

AU - Güran, Tülay

AU - Burtey, Stéphane

AU - Parotte, Marie-Christine

AU - König, Jens

AU - Braun, Alina

AU - Bos, Caro

AU - Ibars Serra, Maria

AU - Rehmann, Holger

AU - Zwartkruis, Fried J T

AU - Renkema, Kirsten Y

AU - Klingel, Karin

AU - Schulze-Bahr, Eric

AU - Schermer, Bernhard

AU - Bergmann, Carsten

AU - Altmüller, Janine

AU - Thiele, Holger

AU - Beck, Bodo B

AU - Dahan, Karin

AU - Sabatini, David

AU - Liebau, Max C

AU - Vargas-Poussou, Rosa

AU - Knoers, Nine V A M

AU - Konrad, Martin

AU - de Baaij, Jeroen H F

N1 - Copyright © 2021 by the American Society of Nephrology.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - Cardiomyopathy, Dilated/genetics

KW - Female

KW - HEK293 Cells

KW - Humans

KW - Hypercalciuria/genetics

KW - Kidney Diseases/genetics

KW - Kidney Tubules, Distal/metabolism

KW - Male

KW - Models, Molecular

KW - Monomeric GTP-Binding Proteins/genetics

KW - Mutation, Missense

KW - Natriuresis/genetics

KW - Nephrocalcinosis/genetics

KW - Pedigree

KW - Protein Conformation

KW - Renal Tubular Transport, Inborn Errors/genetics

KW - Seizures/genetics

KW - Signal Transduction

KW - TOR Serine-Threonine Kinases/metabolism

KW - Whole Exome Sequencing

KW - Whole Genome Sequencing

U2 - 10.1681/ASN.2021030333

DO - 10.1681/ASN.2021030333

M3 - SCORING: Journal article

C2 - 34607910

VL - 32

SP - 2885

EP - 2899

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 11

ER -