Germline mutations in a G protein identify signaling cross-talk in T cells

Ham H 1 , Jing H 1 , Lamborn IT 1 , Kober MM 1 , Koval A 2 , Berchiche YA 3 Show all authors , Anderson DE 4 , Druey KM 5 , Mandl JN 6 , Isidor B 7 , Ferreira CR 8 , Freeman AF 9 , Ganesan S 10 , Karsak M 11 , Mustillo PJ 12 , Teo J 13 , Zolkipli-Cunningham Z 14 , Chatron N 15 , Lecoquierre F 16 , Oler AJ 17 , Schmid JP 18 , Kuhns DB 19 , Xu X 20 , Hauck F 21 , Al-Herz W 22 , Wagner M 23 , Terhal PA 24 , Muurinen M 25 , Barlogis V 26 , Cruz P 17 , Danielson J 1 , Stewart H 27 , Loid P 25 , Rading S 11 , Keren B 28 , Pfundt R 29 , Zarember KA 9 , Vill K 30 , Potocki L 31 , Olivier KN 32 , Lesca G 15 , Faivre L 33 , Wong M 34 , Puel A 35 , Chou J 36 , Tusseau M 37 , Moutsopoulos NM 38 , Matthews HF 39 , Simons C 40 , Taft RJ 41 , Soldatos A 42 , Masle-Farquhar E 43 , Pittaluga S 44 , Brink R 45 , Fink DL 19 , Kong HH 46 , Kabat J 10 , Kim WS 20 , Bierhals T 47 , Meguro K 1 , Hsu AP 9 , Gu J 17 , Stoddard J 48 , Banos-Pinero B 49 , Slack M 50 , Trivellin G 51 , Mazel B 52 , Soomann M 18 , Li S 17 , Watts VJ 53 , Stratakis CA 51 , Rodriguez-Quevedo MF 54 , Bruel AL 33 , Lipsanen-Nyman M 55 , Saultier P 26 , Jain R 56 , Lehalle D 57 , Torres D 1 , Sullivan KE 58 , Barbarot S 59 , Neu A 60 , Duffourd Y 33 , Similuk M 61 , McWalter K 62 , Blanc P 63 , Bézieau S 7 , Jin T 20 , Geha RS 36 , Casanova JL 35 , Makitie OM 25 , Kubisch C 47 , Edery P 15 , Christodoulou J 64 , Germain RN 6 , Goodnow CC 43 , Sakmar TP 3 , Billadeau DD 54 , Küry S 7 , Katanaev VL 2 , Zhang Y 1 , Lenardo MJ 39 , Su HC 1

Affiliations 

  • 1 Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
  • 2 Department of Cell Physiology and Metabolism, Faculty of Medicine, Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland
  • 3 Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY, USA
  • 4 Advanced Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
  • 5 Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, DIR, NIAID, NIH, Bethesda, MD, USA
  • 6 Lymphocyte Biology Section, Laboratory of Immune System Biology, DIR, NIAID, NIH, Bethesda, MD, USA
  • 7 Service de Génétique Médicale, CHU Nantes, Nantes Université, Nantes, France
  • 8 Skeletal Genomics Unit, Metabolic Medicine Branch, DIR, National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD, USA
  • 9 Laboratory of Clinical Immunology and Microbiology, DIR, NIAID, NIH, Bethesda, MD, USA
  • 10 Biological Imaging Section, Research Technologies Branch, DIR, NIAID, NIH, Bethesda, MD 20892, USA
  • 11 Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 12 Nationwide Children's Hospital, Columbus, OH, USA
  • 13 Department of Haematology, The Children's Hospital Westmead, Sydney, New South Wales, Australia
  • 14 Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
  • 15 Service de Génétique, Hospices Civils de Lyon, Lyon, France
  • 16 Université de Rouen Normandie, INSERM U12045 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, FHU-G4 Génomique, Rouen, France
  • 17 Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology (OCICB), NIAID, NIH, Bethesda, MD, USA
  • 18 Division of Immunology, University Children's Hospital Zurich, Zurich, Switzerland
  • 19 Neutrophil Monitoring Lab, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
  • 20 Chemotaxis Signal Section, Laboratory of Immunogenetics, DIR, NIAID, NIH, Rockville, MD, USA
  • 21 Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität (LMU), Munich, Germany
  • 22 Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
  • 23 Institute of Human Genetics, Technical University Munich, School of Medicine and Health, Munich, Germany
  • 24 Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  • 25 Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland
  • 26 APHM, La Timone Children's Hospital, Department of Pediatric Hematology, Immunology, and Oncology, Marseille, France
  • 27 Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals, NHS Foundation Trust, Headington, Oxford, UK
  • 28 Genetic Departement, Assistance Publique - Hôpitaux de Paris.Sorbonne University, Paris, France
  • 29 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
  • 30 LMU University Hospital, Department of Pediatrics, Division of Pediatric Neurology, iSPZ Hauner MUC - Munich University Center for Children with Medical and Developmental Complexity, Dr. von Hauner Children's Hospital, Munich, Germany
  • 31 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  • 32 Pulmonary Branch, Division of Intramural Research, DIR, National Heart Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA
  • 33 Génétique des Anomalies du Développement (GAD), UMR 1231, INSERM, Université Bourgogne-Franche Comté, Dijon, France
  • 34 Department of Allergy and Immunology, The Children's Hospital at Westmead, Sydney, NSW, Australia
  • 35 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
  • 36 Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, United States
  • 37 Genetics Department, Lyon University Hospital, Lyon, France
  • 38 Oral Immunity and Infection Section, DIR, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD, USA
  • 39 Clinical Genomics Program, DIR, NIAID, NIH, Bethesda, MD, USA
  • 40 Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, NSW, Australia
  • 41 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
  • 42 National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA
  • 43 Immunogenomics Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia
  • 44 Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA
  • 45 St. Vincent's Clinical School, UNSW, Sydney, NSW, Australia
  • 46 Cutaneous Microbiome and Inflammation Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA
  • 47 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 48 Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA
  • 49 Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK
  • 50 Division of Allergy and Immunology, Department of Pediatrics, University of Rochester Medical Center and Golisano Children's Hospital, Rochester, NY, USA
  • 51 Section on Endocrinology and Genetics (SEGEN), DIR, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA
  • 52 Centre de Génétique et Centre de Référence "Anomalies du Développement et Syndromes Malformatifs de l'Inter-région Est", FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
  • 53 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
  • 54 Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA
  • 55 Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 56 Clinical Immunology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  • 57 AP-HP Sorbonne Université, UF de Génétique Clinique, Centre de Référence Maladies Rares des Anomalies du Développement et Syndromes Malformatifs, Hôpital Trousseau, Paris, France
  • 58 Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
  • 59 Department of Dermatology, CHU Nantes, INRAE, UMR 1280, PhAN, Nantes Université, Nantes, France
  • 60 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 61 Centralized Sequencing Program, DIR, NIAID, NIH, Bethesda, MD, USA
  • 62 GeneDx, Gaithersburg, MD, USA
  • 63 SeqOIA Laboratory, FMG2025, Paris, France
  • 64 Murdoch Children's Research Institute, Melbourne, Victoria, Australia
Science, 2024 Sep 20;385(6715):eadd8947.
PMID: 39298586 DOI: 10.1126/science.add8947

Abstract

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

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