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

• DOI: 10.1126/science.add8947
• Publication Date: 2024-09-19T18:00:23Z
• Authors: 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 Zolkipl...; Nicolas Chatron; François Lecoquierre; Andrew J. Oler; Jana Pachlopnik S...; 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-Far...; 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. St...; Maria F. Rodrigue...; Ange-Line Bruel; Marita Lipsanen-N...; 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 Casa...; Outi M. Makitie; Christian Kubisch; Patrick Edery; John Christodoulou; Ronald N. Germain; Christopher C. Go...; Thomas P. Sakmar; Daniel D. Billadeau; Sébastien Küry; Vladimir L. Katanaev; Yu Zhang; Michael J. Lenardo; Helen C. Su
• Keywords: MESH: Signal Transduction; 570; MESH: Pedigree; MAP Kinase Signaling System; [SDV]Life Sciences [q-bio]; T-Lymphocytes; Receptors, Antigen, T-Cell; 610; Human Genetics - Radboud University Medical Center - DCMN; MESH: GTP-Binding Protein alpha Subunit; MESH: ras GTPase-Activating Proteins; Phosphatidylinositol 3-Kinases; Cell Movement; MESH: Cell Proliferation; MESH: Germ-Line Mutation; MESH: Receptors; Humans; General; MESH: Cell Movement; MESH: Immunity; Germ-Line Mutation; Cell Proliferation; [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology; MESH: Humans; Gi2; MESH: MAP Kinase Signaling System; MESH: Proto-Oncogene Proteins c-akt; Immunity; MESH: Receptors, Antigen, T-Cell; T-Cell; MESH: GTP-Binding Protein alpha Subunit, Gi2; Pedigree; [SDV] Life Sciences [q-bio]; MESH: T-Lymphocytes; MESH: Phosphatidylinositol 3-Kinases; ras GTPase-Activating Proteins; Antigen; ras Proteins; [SDV.IMM]Life Sciences [q-bio]/Immunology; GTP-Binding Protein alpha Subunit, Gi2; MESH: ras Proteins; Proto-Oncogene Proteins c-akt; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; Signal Transduction

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 heterotrimeric protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients activating had clinical presentations that included impaired immunity. Mutant cell migration and augmented responses T receptor (TCR) stimulation. found mutant influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating RASA2, thereby promoting RAS activation increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated (MAPK) phosphatidylinositol 3-kinase (PI3K)–AKT S6 drive cellular growth proliferation.