PMID- 37057673
OWN - NLM
STAT- MEDLINE
DCOM- 20230724
LR  - 20240320
IS  - 1530-0366 (Electronic)
IS  - 1098-3600 (Linking)
VI  - 25
IP  - 7
DP  - 2023 Jul
TI  - De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.
PG  - 100838
LID - S1098-3600(23)00851-1 [pii]
LID - 10.1016/j.gim.2023.100838 [doi]
AB  - 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.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Reijnders, Margot R F
AU  - Reijnders MRF
AD  - Department of Clinical Genetics, Maastricht University Medical Center, 
      Maastricht, The Netherlands.
FAU - Seibt, Annette
AU  - Seibt A
AD  - Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical 
      Faculty, Heinrich-Heine-University, Dusseldorf, Germany.
FAU - Brugger, Melanie
AU  - Brugger M
AD  - Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, 
      Technical University of Munich, Munich, Germany.
FAU - Lamers, Ideke J C
AU  - Lamers IJC
AD  - Department of Human Genetics, Radboud University Medical Center, Nijmegen, The 
      Netherlands.
FAU - Ott, Torsten
AU  - Ott T
AD  - University Children's Hospital, University Hospital Muenster, Munster, Germany.
FAU - Klaas, Oliver
AU  - Klaas O
AD  - Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
FAU - Horvath, Judit
AU  - Horvath J
AD  - Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
FAU - Rose, Ailsa M S
AU  - Rose AMS
AD  - Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
FAU - Craghill, Isabel M
AU  - Craghill IM
AD  - Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
FAU - Brunet, Theresa
AU  - Brunet T
AD  - 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.
FAU - Graf, Elisabeth
AU  - Graf E
AD  - Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, 
      Technical University of Munich, Munich, Germany.
FAU - Mayerhanser, Katharina
AU  - Mayerhanser K
AD  - Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, 
      Technical University of Munich, Munich, Germany.
FAU - Hellebrekers, Debby
AU  - Hellebrekers D
AD  - Department of Clinical Genetics, Maastricht University Medical Center, 
      Maastricht, The Netherlands.
FAU - Pauck, David
AU  - Pauck D
AD  - Institute of Neuropathology, Medical Faculty, Heinrich-Heine-University, 
      Dusseldorf, Germany.
FAU - Neuen-Jacob, Eva
AU  - Neuen-Jacob E
AD  - Institute of Neuropathology, Medical Faculty, Heinrich-Heine-University, 
      Dusseldorf, Germany.
FAU - Rodenburg, Richard J T
AU  - Rodenburg RJT
AD  - Translational Metabolic Laboratory, Department of Pediatrics, Radboud University 
      Medical Center, Nijmegen, The Netherlands.
FAU - Wieczorek, Dagmar
AU  - Wieczorek D
AD  - Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, 
      Dusseldorf, Germany.
FAU - Klee, Dirk
AU  - Klee D
AD  - Department of Diagnostic and Interventional Radiology, University Hospital, 
      Dusseldorf, Germany.
FAU - Mayatepek, Ertan
AU  - Mayatepek E
AD  - Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical 
      Faculty, Heinrich-Heine-University, Dusseldorf, Germany.
FAU - Driessen, Gertjan
AU  - Driessen G
AD  - Department of Paediatrics, Maastricht University Medical Center, Maastricht, The 
      Netherlands.
FAU - Bindermann, Robert
AU  - Bindermann R
AD  - Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical 
      Faculty, Heinrich-Heine-University, Dusseldorf, Germany.
FAU - Averdunk, Luisa
AU  - Averdunk L
AD  - Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical 
      Faculty, Heinrich-Heine-University, Dusseldorf, Germany.
FAU - Lohmeier, Klaus
AU  - Lohmeier K
AD  - Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical 
      Faculty, Heinrich-Heine-University, Dusseldorf, Germany.
FAU - Sinnema, Margje
AU  - Sinnema M
AD  - Department of Clinical Genetics, Maastricht University Medical Center, 
      Maastricht, The Netherlands.
FAU - Stegmann, Alexander P A
AU  - Stegmann APA
AD  - Department of Clinical Genetics, Maastricht University Medical Center, 
      Maastricht, The Netherlands.
FAU - Roepman, Ronald
AU  - Roepman R
AD  - Department of Human Genetics, Radboud University Medical Center, Nijmegen, The 
      Netherlands.
FAU - Poulter, James A
AU  - Poulter JA
AD  - Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
FAU - Distelmaier, Felix
AU  - Distelmaier F
AD  - Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical 
      Faculty, Heinrich-Heine-University, Dusseldorf, Germany. Electronic address: 
      felix.distelmaier@med.uni-duesseldorf.de.
LA  - eng
GR  - MR/T02044X/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20230411
PL  - United States
TA  - Genet Med
JT  - Genetics in medicine : official journal of the American College of Medical 
      Genetics
JID - 9815831
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (RRAGC protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - Infant
MH  - Fibroblasts/metabolism
MH  - Genetic Diseases, Inborn/genetics
MH  - HEK293 Cells
MH  - *Mechanistic Target of Rapamycin Complex 1/genetics
MH  - *Monomeric GTP-Binding Proteins/genetics/metabolism
MH  - Multiprotein Complexes/genetics
MH  - Mutation, Missense
MH  - *TOR Serine-Threonine Kinases/genetics/metabolism
OTO - NOTNLM
OT  - Cardiomyopathy
OT  - Cortical malformation
OT  - Heart
OT  - Lysosome
OT  - Mitochondrial
OT  - mTORopathy
COIS- Conflict of Interest The authors declare no conflicts of interest.
EDAT- 2023/04/15 06:00
MHDA- 2023/07/10 06:42
CRDT- 2023/04/14 05:58
PHST- 2022/11/17 00:00 [received]
PHST- 2023/03/29 00:00 [revised]
PHST- 2023/04/03 00:00 [accepted]
PHST- 2023/07/10 06:42 [medline]
PHST- 2023/04/15 06:00 [pubmed]
PHST- 2023/04/14 05:58 [entrez]
AID - S1098-3600(23)00851-1 [pii]
AID - 10.1016/j.gim.2023.100838 [doi]
PST - ppublish
SO  - Genet Med. 2023 Jul;25(7):100838. doi: 10.1016/j.gim.2023.100838. Epub 2023 Apr 
      11.