University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Program in Molecular Medicine

Publication Date

2021-03-12

Document Type

Article Preprint

Disciplines

Cardiovascular Diseases | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics

Abstract

Background Over the last decaces, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, ±20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM).

Methods Whole exome and genome sequencings were performed with various subsequent functional analyses of identified RRAGD variants in vitro.

Results In 8 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 additionally suffered from DCM requiring heart transplantation in 3 of them. An additional dominant variant in RRAGD was simultaneously identified in eight members of a large family with a similar renal phenotype. RRAGD encodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include 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 phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

Keywords

Genetics, tubulopathy, hypomagnesemia, dilated cardiomyopathy, rare hereditary disorders

Rights and Permissions

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

DOI of Published Version

10.1101/2021.03.11.434334

Source

bioRxiv 2021.03.11.434334; doi: https://doi.org/10.1101/2021.03.11.434334. Link to preprint on bioRxiv.

Comments

This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

The PDF available for download is Version 2 of this preprint. The complete version history of this preprint is available at bioRxiv.

Full author list omitted for brevity. For the full list of authors, see article.

Journal/Book/Conference Title

bioRxiv

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Share

COinS