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

Margot R F Reijnders; Annette Seibt; Melanie Brugger; Ideke J C Lamers; Torsten Ott; Oliver Klaas; Judit Horváth; Ailsa M S Rose; Isabel M Craghill; Theresa Brunet; Elisabeth Graf; Katharina Mayerhanser; Debby Hellebrekers; David Pauck; Eva Neuen-Jacob; Richard J T Rodenburg; Dagmar Wieczorek; Dirk Klee; Ertan Mayatepek; Gertjan Driessen; Robert Bindermann; Luisa Averdunk; Klaus Lohmeier; Margje Sinnema; Alexander P A Stegmann; Ronald Roepman; James A Poulter; Felix Distelmaier

doi:10.1016/j.gim.2023.100838

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

Genet Med. 2023 Jul;25(7):100838. doi: 10.1016/j.gim.2023.100838. Epub 2023 Apr 11.

Authors

Margot R F Reijnders¹, Annette Seibt², Melanie Brugger³, Ideke J C Lamers⁴, Torsten Ott⁵, Oliver Klaas⁶, Judit Horváth⁶, Ailsa M S Rose⁷, Isabel M Craghill⁷, Theresa Brunet⁸, Elisabeth Graf³, Katharina Mayerhanser³, Debby Hellebrekers¹, David Pauck⁹, Eva Neuen-Jacob⁹, Richard J T Rodenburg¹⁰, Dagmar Wieczorek¹¹, Dirk Klee¹², Ertan Mayatepek², Gertjan Driessen¹³, Robert Bindermann², Luisa Averdunk², Klaus Lohmeier², Margje Sinnema¹, Alexander P A Stegmann¹, Ronald Roepman⁴, James A Poulter⁷, Felix Distelmaier¹⁴

Affiliations

¹ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
² Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
³ Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵ University Children's Hospital, University Hospital Muenster, Münster, Germany.
⁶ Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
⁷ Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
⁸ Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Department of Paediatric Neurology and Developmental Medicine, Hauner Children's Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
⁹ Institute of Neuropathology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
¹⁰ Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹ Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
¹² Department of Diagnostic and Interventional Radiology, University Hospital, Düsseldorf, Germany.
¹³ Department of Paediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁴ Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: [email protected].

PMID: 37057673
DOI: 10.1016/j.gim.2023.100838

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Cardiomyopathy; Cortical malformation; Heart; Lysosome; Mitochondrial; mTORopathy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Fibroblasts / metabolism
Genetic Diseases, Inborn / genetics
HEK293 Cells
Humans
Infant
Mechanistic Target of Rapamycin Complex 1* / genetics
Monomeric GTP-Binding Proteins* / genetics
Monomeric GTP-Binding Proteins* / metabolism
Multiprotein Complexes / genetics
Mutation, Missense
TOR Serine-Threonine Kinases* / genetics
TOR Serine-Threonine Kinases* / metabolism

Substances

Mechanistic Target of Rapamycin Complex 1
Monomeric GTP-Binding Proteins
Multiprotein Complexes
RRAGC protein, human
TOR Serine-Threonine Kinases

Grants and funding

MR/T02044X/1/MRC_/Medical Research Council/United Kingdom