Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Genet Med. 2023 Jul;25(7):100838. doi: 10.1016/j.gim.2023.100838. Epub 2023 Apr 11.
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the 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.
Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with 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.
We identified 3 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 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.
The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.
雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）通过调节细胞生长来响应营养状态。mTORC1 的功能核心是 Rag-GTPase 异二聚体。Rag 异二聚体的一个组成部分是 RagC（Ras 相关 GTP 结合蛋白 C），它由 RRAGC 基因编码。
通过对 3 名患有扩张型心肌病、肝病变和脑异常（包括巨脑回、多小脑回和视隔发育不良）的婴儿进行三核苷酸外显子组测序的遗传检测，确定潜在的疾病病因。在患者来源的皮肤成纤维细胞和 HEK293 细胞模型中进行研究，以研究细胞后果。
我们在 RRAGC 中发现了 3 个新的错义变异（NM_022157.4：c.269C>A，p.（Thr90Asn），c.353C>T，p.（Pro118Leu）和 c.343T>C，p.（Trp115Arg）），这些变异先前被报道为滤泡性淋巴瘤的体细胞发生。携带 p.（Thr90Asn）变异的患者来源的成纤维细胞研究显示细胞体积增大，以及 mTOR 相关 p70S6K（核糖体蛋白 S6 激酶 1）和转录因子 EB 信号的失调。此外，mTOR 的亚细胞定位与代谢状态脱耦联。我们在 HEK293 细胞模型中证实了本研究中描述的所有 RRAGC 变异的关键发现。
上述结果与 mTORC1 途径的组成性过度激活一致。我们的研究确立了 RRAGC 中的新错义变异是一种具有不良预后的早发性 mTOR 病的病因。
