De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood

Introduction Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene. Material and Methods Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in three infants who suffered from dilated cardiomyopathy, hepatopathy and brain abnormalities including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences. Results We identified three de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and TFEB (transcription factor EB) signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key-findings for all RRAGC variants described in this study in a HEK293 cell model. Discussion The above results are in line with a constitutive over-activation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis