Schlingmann, Karl P., Jouret, Francois, Shen, Kuang, Nigam, Anukrati, Arjona, Francisco J., Dafinger, Claudia, Houillier, Pascal, Jones, Deborah P., Kleinerueschkamp, Felix, Oh, Jun, Godefroid, Nathalie, Eltan, Mehmet, Guran, Tulay, Burtey, Stephane, Parotte, Marie-Christine, Koenig, Jens, Braun, Alina, Bos, Caro ORCID: 0000-0001-5016-9435, Serra, Maria Ibars, Rehmann, Holger, Zwartkruis, Fried J. T., Renkema, Kirsten Y., Klingel, Karin, Schulze-Bahr, Eric, Schermer, Bernhard, Bergmann, Carsten, Altmueller, Janine, Thiele, Holger, Beck, Bodo B., Dahan, Karin, Sabatini, David, Liebau, Max C., Vargas-Poussou, Rosa, Knoers, Nine V. A. M., Konrad, Martin and de Baaij, Jeroen H. F. (2021). mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy. J. Am. Soc. Nephrol., 32 (11). S. 2885 - 2900. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schlingmann, Karl P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jouret, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shen, KuangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nigam, AnukratiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arjona, Francisco J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dafinger, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houillier, PascalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, Deborah P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleinerueschkamp, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oh, JunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godefroid, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eltan, MehmetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guran, TulayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burtey, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parotte, Marie-ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, AlinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bos, CaroUNSPECIFIEDorcid.org/0000-0001-5016-9435UNSPECIFIED
Serra, Maria IbarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rehmann, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zwartkruis, Fried J. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renkema, Kirsten Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klingel, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze-Bahr, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergmann, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, Bodo B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahan, KarinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sabatini, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebau, Max C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vargas-Poussou, RosaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knoers, Nine V. A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konrad, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Baaij, Jeroen H. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-606900
DOI: 10.1681/ASN.2021030333
Journal or Publication Title: J. Am. Soc. Nephrol.
Volume: 32
Number: 11
Page Range: S. 2885 - 2900
Date: 2021
Publisher: AMER SOC NEPHROLOGY
Place of Publication: WASHINGTON
ISSN: 1533-3450
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHLORIDE CHANNEL GENE; HYPOMAGNESEMIA; TRPM6; METABOLISM; TRANSPORT; GITELMAN; DISEASE; CLCNKBMultiple languages
Urology & NephrologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60690

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