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RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in
Anastasia Adella1, Sara B van Katwijk1, Pieter A Leermakers1
1Department of Medical BioSciences, Radboudumc, Nijmegen, the Netherlands.
Summary
Gain-of-function variants in the RRAGD gene cause overactivation of mTORC1 signaling, leading to cellular changes in cardiomyocytes. This research sheds light on the mechanisms behind Autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD) and dilated cardiomyopathy (DCM).
Area of Science:
- Molecular Biology
- Cardiology
- Genetics
Background:
- Autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD) is a hereditary disorder linking kidney tubulopathy and dilated cardiomyopathy (DCM).
- The RRAGD gene encodes RagD, a GTPase crucial for amino acid-mediated activation of mTORC1 signaling.
- The precise role of RRAGD gain-of-function variants in DCM pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the hypothesis that RRAGD variants induce mTORC1 overactivation, contributing to DCM.
- To establish and characterize cellular models for studying ADKH-RRAGD.
- To elucidate the molecular mechanisms linking RRAGD variants to cardiac dysfunction.
Main Methods:
- Overexpression of wild-type (WT) and p.(Ser76Leu) RRAGD variants in T-REx HeLa cells to assess mTORC1 signaling.
- Development of a cellular model using genetically edited human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing the mutated RRAGD variant.
- Pharmacological inhibition of mTOR using Torin1.
- Bulk RNA sequencing of hiPSC-CMs.
- Analysis of Ca2+ transient dynamics in cardiomyocytes.
Main Results:
- The RRAGD p.(Ser76Leu) variant sustained mTORC1 target phosphorylation during amino acid starvation in HeLa cells, unlike WT RRAGD.
- Pharmacological mTOR inhibition reversed these effects.
- Mutant hiPSC-CMs exhibited prolonged Ca2+ transients and altered gene expression, including upregulation of cytoskeletal organization and downregulation of muscle development pathways.
- These findings suggest potential cardiomyocyte dedifferentiation.
Conclusions:
- Gain-of-function RRAGD variants lead to mTORC1 activation.
- This activation impairs intracellular Ca2+ handling and alters transcriptional programs in cardiomyocytes, potentially contributing to DCM.
- The study provides a cellular basis for understanding ADKH-RRAGD and its cardiac manifestations.
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