University of Massachusetts Medical School Faculty Publications

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Program in Molecular Medicine

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


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.


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

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bioRxiv 2021.03.11.434334; doi: Link to preprint on bioRxiv.


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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.