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

Hyoungjun Ham; Huie Jing; Ian T Lamborn; Megan M Kober; Alexey Koval; Yamina A Berchiche; D Eric Anderson; Kirk M Druey; Judith N Mandl; Bertrand Isidor; Carlos R Ferreira; Alexandra F Freeman; Sundar Ganesan; Meliha Karsak; Peter J Mustillo; Juliana Teo; Zarazuela Zolkipli-Cunningham; Nicolas Chatron; François Lecoquierre; Andrew J Oler; Jana Pachlopnik Schmid; Douglas B Kuhns; Xuehua Xu; Fabian Hauck; Waleed Al-Herz; Matias Wagner; Paulien A Terhal; Mari Muurinen; Vincent Barlogis; Phillip Cruz; Jeffrey Danielson; Helen Stewart; Petra Loid; Sebastian Rading; Boris Keren; Rolph Pfundt; Kol A Zarember; Katharina Vill; Lorraine Potocki; Kenneth N Olivier; Gaetan Lesca; Laurence Faivre; Melanie Wong; Anne Puel; Janet Chou; Maud Tusseau; Niki M Moutsopoulos; Helen F Matthews; Cas Simons; Ryan J Taft; Ariane Soldatos; Etienne Masle-Farquhar; Stefania Pittaluga; Robert Brink; Danielle L Fink; Heidi H Kong; Juraj Kabat; Woo Sung Kim; Tatjana Bierhals; Kazuyuki Meguro; Amy P Hsu; Jingwen Gu; Jennifer Stoddard; Benito Banos-Pinero; Maria Slack; Giampaolo Trivellin; Benoît Mazel; Maarja Soomann; Samuel Li; Val J Watts; Constantine A Stratakis; Maria F Rodriguez-Quevedo; Ange-Line Bruel; Marita Lipsanen-Nyman; Paul Saultier; Rashmi Jain; Daphne Lehalle; Daniel Torres; Kathleen E Sullivan; Sébastien Barbarot; Axel Neu; Yannis Duffourd; Morgan Similuk; Kirsty McWalter; Pierre Blanc; Stéphane Bézieau; Tian Jin; Raif S Geha; Jean-Laurent Casanova; Outi M Makitie; Christian Kubisch; Patrick Edery; John Christodoulou; Ronald N Germain; Christopher C Goodnow; Thomas P Sakmar; Daniel D Billadeau; Sébastien Küry; Vladimir L Katanaev; Yu Zhang; Michael J Lenardo; Helen C Su

doi:10.1126/science.add8947

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

Science. 2024 Sep 20;385(6715):eadd8947. doi: 10.1126/science.add8947. Epub 2024 Sep 20.

Authors

Hyoungjun Ham^#^{1

2

3}, Huie Jing^#^{1

2}, Ian T Lamborn^#^{1

2

4}, Megan M Kober^#^{1

2}, Alexey Koval^#⁵, Yamina A Berchiche^#⁶, D Eric Anderson⁷, Kirk M Druey⁸, Judith N Mandl⁹, Bertrand Isidor^{10

11}, Carlos R Ferreira¹², Alexandra F Freeman¹³, Sundar Ganesan¹⁴, Meliha Karsak^{15

16}, Peter J Mustillo^{17

18}, Juliana Teo¹⁹, Zarazuela Zolkipli-Cunningham^{20

21}, Nicolas Chatron^{22

23}, François Lecoquierre²⁴, Andrew J Oler²⁵, Jana Pachlopnik Schmid^{26

27}, Douglas B Kuhns²⁸, Xuehua Xu²⁹, Fabian Hauck³⁰, Waleed Al-Herz^{31

32}, Matias Wagner^{33

34

35}, Paulien A Terhal³⁶, Mari Muurinen^{37

38

39}, Vincent Barlogis^{40

41}, Phillip Cruz²⁵, Jeffrey Danielson^{1

2}, Helen Stewart⁴², Petra Loid^{37

38

39}, Sebastian Rading^{15

16}, Boris Keren^{43

44}, Rolph Pfundt⁴⁵, Kol A Zarember¹³, Katharina Vill⁴⁶, Lorraine Potocki^{47

48}, Kenneth N Olivier⁴⁹, Gaetan Lesca^{22

23}, Laurence Faivre^{50

51}, Melanie Wong⁵², Anne Puel^{53

54

55}, Janet Chou⁵⁶, Maud Tusseau^{57

58}, Niki M Moutsopoulos⁵⁹, Helen F Matthews^{2

60}, Cas Simons^{61

62}, Ryan J Taft^{63

64}, Ariane Soldatos⁶⁵, Etienne Masle-Farquhar^{66

67}, Stefania Pittaluga⁶⁸, Robert Brink^{69

70}, Danielle L Fink²⁸, Heidi H Kong⁷¹, Juraj Kabat¹⁴, Woo Sung Kim²⁹, Tatjana Bierhals¹⁶, Kazuyuki Meguro^{1

2}, Amy P Hsu¹³, Jingwen Gu²⁵, Jennifer Stoddard⁷², Benito Banos-Pinero⁷³, Maria Slack⁷⁴, Giampaolo Trivellin⁷⁵, Benoît Mazel^{51

76}, Maarja Soomann²⁶, Samuel Li²⁵, Val J Watts⁷⁷, Constantine A Stratakis⁷⁵, Maria F Rodriguez-Quevedo³, Ange-Line Bruel^{50

78}, Marita Lipsanen-Nyman³⁸, Paul Saultier^{40

79}, Rashmi Jain⁸⁰, Daphne Lehalle⁸¹, Daniel Torres^{1

2}, Kathleen E Sullivan⁸², Sébastien Barbarot⁸³, Axel Neu⁸⁴, Yannis Duffourd^{50

78}, Morgan Similuk⁸⁵, Kirsty McWalter⁸⁶, Pierre Blanc⁴⁴, Stéphane Bézieau^{10

11}, Tian Jin²⁹, Raif S Geha⁵⁶, Jean-Laurent Casanova^{53

54

55

87

88}, Outi M Makitie^{37

38

39}, Christian Kubisch^{16

89}, Patrick Edery^{22

90}, John Christodoulou^{62

91

92}, Ronald N Germain⁹, Christopher C Goodnow^{66

93}, Thomas P Sakmar^{6

94}, Daniel D Billadeau³, Sébastien Küry^#^{10

11}, Vladimir L Katanaev^#^{5

95}, Yu Zhang^#^{1

2}, Michael J Lenardo^{2

4

60}, Helen C Su^{1

2

4}

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 Clinical Genomics Program, DIR, NIAID, NIH, Bethesda, MD, USA.
³ Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA.
⁴ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Cell Physiology and Metabolism, Faculty of Medicine, Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland.
⁶ Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY, USA.
⁷ Advanced Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
⁸ Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, DIR, NIAID, NIH, Bethesda, MD, USA.
⁹ Lymphocyte Biology Section, Laboratory of Immune System Biology, DIR, NIAID, NIH, Bethesda, MD, USA.
¹⁰ Service de Génétique Médicale, CHU Nantes, Nantes Université, Nantes, France.
¹¹ L'Institut du Thorax, CHU Nantes, INSERM UMR 1087/CNRS UMR 6291, Nantes Université, Nantes, France.
¹² Skeletal Genomics Unit, Metabolic Medicine Branch, DIR, National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD, USA.
¹³ Laboratory of Clinical Immunology and Microbiology, DIR, NIAID, NIH, Bethesda, MD, USA.
¹⁴ Biological Imaging Section, Research Technologies Branch, DIR, NIAID, NIH, Bethesda, MD 20892, USA.
¹⁵ Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Nationwide Children's Hospital, Columbus, OH, USA.
¹⁸ The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁹ Department of Haematology, The Children's Hospital Westmead, Sydney, New South Wales, Australia.
²⁰ Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²¹ Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²² Service de Génétique, Hospices Civils de Lyon, Lyon, France.
²³ Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle, CNRS UMR 5261, INSERM U1315, Université Claude Bernard Lyon 1, Lyon, France.
²⁴ Université de Rouen Normandie, INSERM U12045 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, FHU-G4 Génomique, Rouen, France.
²⁵ Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology (OCICB), NIAID, NIH, Bethesda, MD, USA.
²⁶ Division of Immunology, University Children's Hospital Zurich, Zurich, Switzerland.
²⁷ Pediatric Immunology, University of Zurich, Zurich, Switzerland.
²⁸ Neutrophil Monitoring Lab, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
²⁹ Chemotaxis Signal Section, Laboratory of Immunogenetics, DIR, NIAID, NIH, Rockville, MD, USA.
³⁰ Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
³¹ Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
³² Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait.
³³ Institute of Human Genetics, Technical University Munich, School of Medicine and Health, Munich, Germany.
³⁴ Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
³⁵ Department of Pediatrics, Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, University Hospital of Munich, Munich, Germany.
³⁶ Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
³⁷ Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland.
³⁸ Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³⁹ Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
⁴⁰ APHM, La Timone Children's Hospital, Department of Pediatric Hematology, Immunology, and Oncology, Marseille, France.
⁴¹ Aix-Marseille University, EA 3279 Research Unit, Marseille, France.
⁴² Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals, NHS Foundation Trust, Headington, Oxford, UK.
⁴³ Genetic Departement, Assistance Publique - Hôpitaux de Paris.Sorbonne University, Paris, France.
⁴⁴ SeqOIA Laboratory, FMG2025, Paris, France.
⁴⁵ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands.
⁴⁶ 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.
⁴⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴⁸ Texas Children's Hospital, Houston, TX, USA.
⁴⁹ Pulmonary Branch, Division of Intramural Research, DIR, National Heart Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA.
⁵⁰ Génétique des Anomalies du Développement (GAD), UMR 1231, INSERM, Université Bourgogne-Franche Comté, Dijon, France.
⁵¹ 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.
⁵² Department of Allergy and Immunology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁵³ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
⁵⁴ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, INSERM U1163, Paris, France.
⁵⁵ Imagine Institute, University of Paris Cité, Paris, France.
⁵⁶ Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
⁵⁷ Genetics Department, Lyon University Hospital, Lyon, France.
⁵⁸ The International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France.
⁵⁹ Oral Immunity and Infection Section, DIR, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD, USA.
⁶⁰ Molecular Development of the Immune System Section, Laboratory of Immune System Biology, DIR, NIAID, NIH, Bethesda, MD, USA.
⁶¹ Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, NSW, Australia.
⁶² Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁶³ Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
⁶⁴ Illumina, San Diego, CA, USA.
⁶⁵ National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA.
⁶⁶ Immunogenomics Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁶⁷ School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
⁶⁸ Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
⁶⁹ St. Vincent's Clinical School, UNSW, Sydney, NSW, Australia.
⁷⁰ B Cell Biology Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁷¹ Cutaneous Microbiome and Inflammation Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA.
⁷² Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA.
⁷³ Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.
⁷⁴ Division of Allergy and Immunology, Department of Pediatrics, University of Rochester Medical Center and Golisano Children's Hospital, Rochester, NY, USA.
⁷⁵ Section on Endocrinology and Genetics (SEGEN), DIR, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA.
⁷⁶ Centre de Référence Déficiences Intellectuelles de Causes Rares, CHU Dijon Bourgogne, Dijon, France.
⁷⁷ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
⁷⁸ Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
⁷⁹ Aix-Marseille University, INSERM, National Research Institute for Agriculture, Food and Environment (INRAe), Cardiovascular and Nutrition Research Center (C2VN), Marseille, France.
⁸⁰ Clinical Immunology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁸¹ AP-HP Sorbonne Université, UF de Génétique Clinique, Centre de Référence Maladies Rares des Anomalies du Développement et Syndromes Malformatifs, Hôpital Trousseau, Paris, France.
⁸² Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸³ Department of Dermatology, CHU Nantes, INRAE, UMR 1280, PhAN, Nantes Université, Nantes, France.
⁸⁴ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸⁵ Centralized Sequencing Program, DIR, NIAID, NIH, Bethesda, MD, USA.
⁸⁶ GeneDx, Gaithersburg, MD, USA.
⁸⁷ Howard Hughes Medical Institute, New York, NY, USA.
⁸⁸ Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
⁸⁹ Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁹⁰ Centre de Recherche en Neurosciences de Lyon, Inserm U1028, UMR CNRS 5292, Université Claude Bernard Lyon 1, Lyon, France.
⁹¹ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
⁹² Specialty of Child and Adolescent Health, University of Sydney, Sydney, Australia.
⁹³ Cellular Genomics Futures Institute, Sydney, NSW, Australia.
⁹⁴ Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Stockholm, Sweden.
⁹⁵ Institute of Life Sciences and Biomedicine, Far Eastern Federal University, Vladivostok, Russia.

^# Contributed equally.

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 G_αi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G_αi2 mutations had clinical presentations that included impaired immunity. Mutant G_αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G_αi2 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.

MeSH terms

Cell Movement / genetics
Cell Proliferation
GTP-Binding Protein alpha Subunit, Gi2* / genetics
Germ-Line Mutation*
Humans
Immunity / genetics
MAP Kinase Signaling System
Pedigree
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Receptors, Antigen, T-Cell* / metabolism
Signal Transduction
T-Lymphocytes* / immunology
T-Lymphocytes* / metabolism
ras GTPase-Activating Proteins* / genetics
ras Proteins / genetics
ras Proteins / metabolism

Substances

GNAI2 protein, human
GTP-Binding Protein alpha Subunit, Gi2
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
ras GTPase-Activating Proteins
ras Proteins
RASA2 protein, human
Receptors, Antigen, T-Cell