RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.
A, A., SB, v.K., PA, L., WB, v.H., H, d.R., J, I., S, H., L, N., TP, d.B., & E, v.R. (2026). RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.. FASEB journal : official publication of the Federation of American Societies for Experimental Biolog. https://doi.org/10.1096/fj.202501099RR
A A, SB vK, PA L, WB vH, H dR, J I, et al. RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.. FASEB journal : official publication of the Federation of American Societies for Experimental Biolog. 2026; doi: 10.1096/fj.202501099RR
A A, SB vK, PA L, et al. RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.[J]. FASEB journal : official publication of the Federation of American Societies for Experimental Biolog. 2026. DOI: 10.1096/fj.202501099RR.
@article{a2026,
author = {Adella A and van Katwijk SB and Leermakers PA and van Ham WB and de Ruiter H and Ilgutytė J and Hendrickx S and Nijland L and de Boer TP and van Rooij E},
title = {RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biolog},
year = {2026},
doi = {10.1096/fj.202501099RR},
note = {PMID: 42329298},
}
TY - JOUR AU - Adella A AU - van Katwijk SB AU - Leermakers PA AU - van Ham WB AU - de Ruiter H AU - Ilgutytė J AU - Hendrickx S AU - Nijland L AU - de Boer TP AU - van Rooij E TI - RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes. T2 - FASEB journal : official publication of the Federation of American Societies for Experimental Biolog PY - 2026 DO - 10.1096/fj.202501099RR AN - PMID:42329298 ER -
Autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD) is a hereditary disorder characterized by kidney tubulopathy and dilated cardiomyopathy (DCM). RagD, encoded by the RRAGD gene, is a small GTPase involved in activating the mechanistic target of rapamycin complex 1 (mTORC1) by amino acids. Although several gain-of-function variants in the RRAGD gene have been identified, their contributions to DCM remain unclear. Here, we hypothesize that these RRAGD variants induce mTORC1 overactivation, thereby contributing to the manifestation of DCM. To investigate this, we established T-REx HeLa cell lines that overexpress the RRAGD p.(Ser76Leu) or the wild-type (WT) variant to assess the effects on mTORC1 signaling. Additionally, we developed the first cellular model of ADKH-RRAGD utilizing genetically edited human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that express the mutated variant. Our data indicate that the RRAGD p.(Ser76Leu) variant maintains the phosphorylation of mTORC1 targets (i.e., S6K, 4E-BP1, and TFEB) during amino acid starvation, in contrast to RRAGD WT in T-REx HeLa cells. The pharmacological inhibition of mTOR with Torin1 reversed these changes. In 2D-cultured RRAGDWT/p.(Ser76Leu) hiPSC-CMs, mTORC1 remained responsive to amino acid starvation. Results from bulk RNA sequencing showed an upregulation of pathways associated with cytoskeletal organization and a downregulation of muscle development in RRAGDWT/p.(Ser76Leu) hiPSC-CMs. Moreover, a prolonged duration of Ca2+ transients was observed in the mutant cardiomyocytes. Altogether, our data demonstrate that gain-of-function variants in RRAGD cause mTORC1 activation in T-REx HeLa cells. Consequently, cardiomyocytes develop impaired intracellular Ca2+ clearance and activation of transcriptional programs, suggesting dedifferentiation.