OpenLB
Open Library of Bioscience
Advanced Search
European journal of human genetics : EJHG
Dec 30, 2024;

RICTOR variants are associated with neurodevelopmental disorders.

Raphael Carapito, Anne Molitor, Lisa Pavinato, Alaa Skeyni, Magalie Lambert, Ang��lique Pichot, Jiuhong Jiang, Perrine Spinnhirny, Lucie Zimmermann, Philippe Boucher, Clara W T Chung, Noha Elserafy, Edward M Blair, Dong Li, Bhoj Elisabeth, Urania Kotzaeridou, Stephanie Karch, Matias Wagner, Roelineke J Lunsing, Rolph Pfundt, Kym M Boycott, Ange-Line Bruel, Fr��d��ric Tran Mau-Them, S��bastien Moutton, Valerio Conti, Davide Mei, Valentina Cetica, Renzo Guerrini, Theresa Brunet, Patrick Rump, Alessandro Mussa, Alfredo Brusco, Gabrielle Lemire, Bert B A de Vries, Zhichao Miao, Bertrand Isidor, Seiamak Bahram
Author Information
  1. Raphael Carapito: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France. carapito@unistra.fr. ORCID
  2. Anne Molitor: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.
  3. Lisa Pavinato: Department of Medical Sciences, University of Turin, 10126, Turin, Italy. ORCID
  4. Alaa Skeyni: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.
  5. Magalie Lambert: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France. ORCID
  6. Ang��lique Pichot: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France. ORCID
  7. Jiuhong Jiang: Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China.
  8. Perrine Spinnhirny: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.
  9. Lucie Zimmermann: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.
  10. Philippe Boucher: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.
  11. Clara W T Chung: Department of Clinical Genetics, Liverpool Hospital, Liverpool, NSW, Australia. ORCID
  12. Noha Elserafy: Department of Clinical Genetics, Liverpool Hospital, Liverpool, NSW, Australia. ORCID
  13. Edward M Blair: NIHR Oxford Biomedical Research Centre, Oxford, UK.
  14. Dong Li: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. ORCID
  15. Bhoj Elisabeth: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  16. Urania Kotzaeridou: Division of Child Neurology and Inherited Metabolic Diseases, Department of Pediatrics, Heidelberg University Hospital, 69120, Heidelberg, Germany.
  17. Stephanie Karch: Division of Child Neurology and Inherited Metabolic Diseases, Department of Pediatrics, Heidelberg University Hospital, 69120, Heidelberg, Germany.
  18. Matias Wagner: Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. ORCID
  19. Roelineke J Lunsing: University of Groningen, University Medical Center Groningen, Department of Paediatric Neurology, Groningen, The Netherlands.
  20. Rolph Pfundt: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
  21. Kym M Boycott: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
  22. Ange-Line Bruel: Unit�� Fonctionnelle Innovation en Diagnostic g��nomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. ORCID
  23. Fr��d��ric Tran Mau-Them: Unit�� Fonctionnelle Innovation en Diagnostic g��nomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. ORCID
  24. S��bastien Moutton: UMR1231 GAD, Inserm - Universit�� Bourgogne-Franche Comt��, Dijon, France. ORCID
  25. Valerio Conti: Neuroscience Department, Meyer Children's Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy.
  26. Davide Mei: Neuroscience Department, Meyer Children's Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy.
  27. Valentina Cetica: Neuroscience Department, Meyer Children's Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy.
  28. Renzo Guerrini: Neuroscience Department, Meyer Children's Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy.
  29. Theresa Brunet: Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. ORCID
  30. Patrick Rump: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. ORCID
  31. Alessandro Mussa: Pediatric Clinical Genetics Unit, Regina Margherita Children's Hospital, Department of Public Health and Pediatric Sciences, University of Torino, piazza Polonia 94, 10126, Torino, Italy. ORCID
  32. Alfredo Brusco: Department of Neurosciences Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy. ORCID
  33. Gabrielle Lemire: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
  34. Bert B A de Vries: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. ORCID
  35. Zhichao Miao: GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China.
  36. Bertrand Isidor: Institut du thorax, Nantes Universit��, CHU de Nantes, CNRS, INSERM, Nantes, France.
  37. Seiamak Bahram: Laboratoire d'ImmunoRhumatologie Mol��culaire, plateforme GENOMAX, INSERM UMR_S 1109, Facult�� de M��decine, F��d��ration Hospitalo-Universitaire OMICARE, F��d��ration de M��decine Translationnelle de Strasbourg (FMTS), Institut Th��matique Interdisciplinaire TRANSPLANTEX NG, Universit�� de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France. siamak@unistra.fr. ORCID
PMID: 39738822 DOI: 10.1038/s41431-024-01774-w

Abstract

RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTOR gene. The phenotypic presentation is diverse with associated features including growth failure, feeding difficulties, abnormal behavior, seizure, hypertonia, brain anomalies and various other congenital organ and skeletal malformations. All patients carried de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3���kb deletion encompassing RICTOR. The mTORC2 pathway was hyperactivated in a patient's fibroblasts carrying a missense variant, while the expression of RICTOR remained unchanged, indicating a gain-of-function mechanism. RNA sequencing on RICTOR knock-out mouse embryonic fibroblasts confirmed the potential role of RICTOR in neuronal cell development.

References

  1. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BWM, Willemsen MH, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344���7. [DOI: 10.1038/nature13394]
  2. Deciphering Developmental Disorders S. Prevalence and architecture of de novo mutations in developmental disorders. Nature 2017;542:433���8.
  3. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960���76. [DOI: 10.1016/j.cell.2017.02.004]
  4. Crino PB. mTOR: A pathogenic signaling pathway in developmental brain malformations. Trends Mol Med. 2011;17:734���42. [DOI: 10.1016/j.molmed.2011.07.008]
  5. Bockaert J, Marin P. mTOR in brain physiology and pathologies. Physiol Rev. 2015;95:1157���87. [DOI: 10.1152/physrev.00038.2014]
  6. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471���84. [DOI: 10.1016/j.cell.2006.01.016]
  7. Kang SA, Pacold ME, Cervantes CL, Lim D, Lou HJ, Ottina K, et al. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science. 2013;341:1236566. [DOI: 10.1126/science.1236566]
  8. Nguyen LH, Brewster AL, Clark ME, Regnier-Golanov A, Sunnen CN, Patil VV, et al. mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia. Epilepsia. 2015;56:636���46. [DOI: 10.1111/epi.12946]
  9. Tsai PT, Rudolph S, Guo C, Ellegood J, Gibson JM, Schaeffer SM, et al. Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors. Cell Rep. 2018;25:357���67 e354. [DOI: 10.1016/j.celrep.2018.09.039]
  10. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 2006;11:583���9. [DOI: 10.1016/j.devcel.2006.08.013]
  11. Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, et al. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci. 2013;16:441���8. [DOI: 10.1038/nn.3351]
  12. Carson RP, Fu C, Winzenburger P, Ess KC. Deletion of Rictor in neural progenitor cells reveals contributions of mTORC2 signaling to tuberous sclerosis complex. Hum Mol Genet. 2013;22:140���52. [DOI: 10.1093/hmg/dds414]
  13. Siuta MA, Robertson SD, Kocalis H, Saunders C, Gresch PJ, Khatri V, et al. Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice. PLoS Biol. 2010;8:e1000393. [DOI: 10.1371/journal.pbio.1000393]
  14. Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y, Nishimura F, Kakiuchi C, et al. Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing. Am J Med Genet B Neuropsychiatr Genet. 2017;174:712���23. [DOI: 10.1002/ajmg.b.32559]
  15. Chen X, Liu M, Tian Y, Li J, Qi Y, Zhao D, et al. Cryo-EM structure of human mTOR complex 2. Cell Res. 2018;28:518���28. [DOI: 10.1038/s41422-018-0029-3]
  16. Yu Z, Chen J, Takagi E, Wang F, Saha B, Liu X, et al. Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt. J Biol Chem. 2022;298:102288. [DOI: 10.1016/j.jbc.2022.102288]
  17. Cameron AJ, Linch MD, Saurin AT, Escribano C, Parker PJ. mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem J. 2011;439:287���97. [DOI: 10.1042/BJ20110678]
  18. Tatebe H, Murayama S, Yonekura T, Hatano T, Richter D, Furuya T, et al. Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit. Elife. 2017;6:e19594. [DOI: 10.7554/eLife.19594]
  19. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098���101. [DOI: 10.1126/science.1106148]
  20. Chen L, Xu B, Liu L, Liu C, Luo Y, Chen X, et al. Both mTORC1 and mTORC2 are involved in the regulation of cell adhesion. Oncotarget. 2015;6:7136���50. [DOI: 10.18632/oncotarget.3044]
  21. Scaiola A, Mangia F, Imseng S, Boehringer D, Berneiser K, Shimobayashi M, et al. The 3.2-A resolution structure of human mTORC2. Sci Adv. 2020;6:eabc1251. [DOI: 10.1126/sciadv.abc1251]

Grants

  1. ANR-10-IDEX-0002/Agence Nationale de la Recherche (French National Research Agency)
  2. ANR-20-SFRI-0012/Agence Nationale de la Recherche (French National Research Agency)
  3. ANR-10-IDEX-0002/Agence Nationale de la Recherche (French National Research Agency)
  4. ANR-20-SFRI-0012/Agence Nationale de la Recherche (French National Research Agency)
Journal Article
Article has an altmetric score of 2

Word Cloud

Created with Highcharts 10.0.0RICTORvariantsdevelopmentmTORC2cellgrowthbrainpatientscarryingassociatedincludingonemissensefibroblastskeycomponentsignalingcomplexinvolvedregulationproliferationsurvivalhighlyexpressedneuronsnecessaryreporteightunrelatedpresentingintellectualdisabilityand/ordelaygenephenotypicpresentationdiversefeaturesfailurefeedingdifficultiesabnormalbehaviorseizurehypertoniaanomaliesvariouscongenitalorganskeletalmalformationscarrieddenovoheterozygousinheritedaffectedparentthreefourloss-of-function3���kbdeletionencompassingpathwayhyperactivatedpatient'svariantexpressionremainedunchangedindicatinggain-of-functionmechanismRNAsequencingknock-outmouseembryonicconfirmedpotentialroleneuronalneurodevelopmentaldisorders

Similar Articles

Cited By