{"doi":"10.1126/science.add8947","title":"Germline mutations in a G protein identify signaling cross-talk in T cells","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.","journal":"Science","year":2024,"id":423451,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":476875,"name":"Huie Jing","orcid":"0000-0001-6283-3452","position":1,"is_corresponding":false},{"id":1218568,"name":"Ian T. Lamborn","orcid":"0009-0006-1490-3667","position":2,"is_corresponding":false},{"id":1218569,"name":"M. Kober","orcid":"0000-0003-3909-9573","position":3,"is_corresponding":false},{"id":780206,"name":"Alexey Koval","orcid":"0000-0002-8920-4426","position":4,"is_corresponding":false},{"id":1218570,"name":"Yamina A. Berchiche","orcid":"0000-0002-9559-9209","position":5,"is_corresponding":false},{"id":281961,"name":"David E. Anderson","orcid":"0000-0002-6838-0201","position":6,"is_corresponding":false},{"id":369508,"name":"Kirk M. Druey","orcid":"0000-0002-5834-6501","position":7,"is_corresponding":false},{"id":476877,"name":"Judith N. Mandl","orcid":"0000-0002-6512-3437","position":8,"is_corresponding":false},{"id":242573,"name":"Bertrand Isidor","orcid":"0000-0001-6480-126X","position":9,"is_corresponding":false},{"id":232561,"name":"Carlos R. Ferreira","orcid":"0000-0002-2697-1046","position":10,"is_corresponding":false},{"id":246527,"name":"Alexandra F. Freeman","orcid":"0000-0001-7005-8345","position":11,"is_corresponding":false},{"id":246602,"name":"Sundar Ganesan","orcid":"0000-0003-1132-2016","position":12,"is_corresponding":false},{"id":1218571,"name":"Meliha Karsak","orcid":"0000-0001-6612-6317","position":13,"is_corresponding":false},{"id":792305,"name":"Peter Mustillo","orcid":"0000-0002-8420-8655","position":14,"is_corresponding":false},{"id":991965,"name":"Juliana Teo","orcid":"0000-0002-2895-0214","position":15,"is_corresponding":false},{"id":301132,"name":"Zarazuela Zolkipli‐Cunningham","orcid":"0000-0002-0743-8879","position":16,"is_corresponding":false},{"id":325746,"name":"Nicolas Chatron","orcid":"0000-0003-0538-0981","position":17,"is_corresponding":false},{"id":699185,"name":"François Lecoquierre","orcid":"0000-0002-9110-1856","position":18,"is_corresponding":false},{"id":104191,"name":"Andrew J. Oler","orcid":"0000-0002-6310-0434","position":19,"is_corresponding":false},{"id":641865,"name":"Jana Pachlopnik Schmid","orcid":"0000-0002-6653-9047","position":20,"is_corresponding":false},{"id":231246,"name":"Douglas B. Kuhns","orcid":"0000-0002-9971-0760","position":21,"is_corresponding":false},{"id":570026,"name":"Xuehua Xu","orcid":"0000-0002-3863-9593","position":22,"is_corresponding":false},{"id":106368,"name":"Fabian Hauck","orcid":"0000-0001-9644-2003","position":23,"is_corresponding":false},{"id":263174,"name":"Waleed Al–Herz","orcid":"0000-0003-4244-4489","position":24,"is_corresponding":false},{"id":282681,"name":"Matias Wagner","orcid":"0000-0002-4454-8823","position":25,"is_corresponding":false},{"id":489448,"name":"Paulien A. Terhal","orcid":null,"position":26,"is_corresponding":false},{"id":1218572,"name":"Mari Muurinen","orcid":"0009-0008-5595-4334","position":27,"is_corresponding":false},{"id":1170894,"name":"Vincent Barlogis","orcid":"0000-0001-9645-3968","position":28,"is_corresponding":false},{"id":582605,"name":"Phillip Cruz","orcid":"0000-0001-7010-7645","position":29,"is_corresponding":false},{"id":426521,"name":"Jeffrey J. Danielson","orcid":"0000-0003-1916-3806","position":30,"is_corresponding":false},{"id":1218573,"name":"Helen Stewart","orcid":"0000-0001-8267-8373","position":31,"is_corresponding":false},{"id":449953,"name":"Petra Loid","orcid":"0000-0002-2708-0878","position":32,"is_corresponding":false},{"id":1219146,"name":"Sebastian Rading","orcid":null,"position":33,"is_corresponding":false},{"id":242574,"name":"Boris Keren","orcid":"0000-0001-6172-8247","position":34,"is_corresponding":false},{"id":360998,"name":"Rolph Pfundt","orcid":"0000-0002-0584-4398","position":35,"is_corresponding":false},{"id":231230,"name":"Kol A. Zarember","orcid":"0000-0002-9624-7096","position":36,"is_corresponding":false},{"id":1218574,"name":"Katharina Vill","orcid":"0000-0003-1925-7538","position":37,"is_corresponding":false},{"id":355068,"name":"Lorraine Potocki","orcid":null,"position":38,"is_corresponding":false},{"id":105506,"name":"Kenneth N. Olivier","orcid":null,"position":39,"is_corresponding":false},{"id":323128,"name":"Gaëtan Lesca","orcid":"0000-0001-7691-9492","position":40,"is_corresponding":false},{"id":242571,"name":"Laurence Faivre","orcid":"0000-0001-9770-444X","position":41,"is_corresponding":false},{"id":852568,"name":"Melanie Wong","orcid":"0000-0002-5984-043X","position":42,"is_corresponding":false},{"id":104226,"name":"Anne Puel","orcid":"0000-0003-2603-0323","position":43,"is_corresponding":false},{"id":11547,"name":"Janet Chou","orcid":"0000-0002-4610-2657","position":44,"is_corresponding":false},{"id":1219147,"name":"Maud Tusseau","orcid":null,"position":45,"is_corresponding":false},{"id":278228,"name":"Niki M. Moutsopoulos","orcid":"0000-0002-7365-6735","position":46,"is_corresponding":false},{"id":170628,"name":"Helen Matthews","orcid":null,"position":47,"is_corresponding":false},{"id":306937,"name":"Cas Simons","orcid":"0000-0003-3147-8042","position":48,"is_corresponding":false},{"id":72309,"name":"Ryan J. Taft","orcid":"0000-0003-4538-3343","position":49,"is_corresponding":false},{"id":360802,"name":"Ariane Soldatos","orcid":"0000-0003-3570-5230","position":50,"is_corresponding":false},{"id":1218575,"name":"Etienne Masle‐Farquhar","orcid":"0000-0001-9355-8027","position":51,"is_corresponding":false},{"id":225661,"name":"Stefania Pittaluga","orcid":"0000-0001-7688-1439","position":52,"is_corresponding":false},{"id":557336,"name":"Robert Brink","orcid":"0000-0002-9586-3655","position":53,"is_corresponding":false},{"id":231229,"name":"Danielle Fink","orcid":"0000-0002-7502-7385","position":54,"is_corresponding":false},{"id":29111,"name":"Heidi H. Kong","orcid":"0000-0003-4424-064X","position":55,"is_corresponding":false},{"id":243363,"name":"Juraj Kabát","orcid":"0000-0001-8636-542X","position":56,"is_corresponding":false},{"id":1218576,"name":"Woo Sung Kim","orcid":"0000-0002-4396-4403","position":57,"is_corresponding":false},{"id":567690,"name":"Tatjana Bierhals","orcid":"0000-0002-6103-105X","position":58,"is_corresponding":false},{"id":1218577,"name":"Kazuyuki Meguro","orcid":"0009-0006-5225-4530","position":59,"is_corresponding":false},{"id":362027,"name":"Amy P. Hsu","orcid":"0000-0001-6841-2122","position":60,"is_corresponding":false},{"id":104192,"name":"Jingwen Gu","orcid":"0000-0003-2258-3131","position":61,"is_corresponding":false},{"id":325549,"name":"Jennifer Stoddard","orcid":"0000-0002-2137-9158","position":62,"is_corresponding":false},{"id":1219148,"name":"Benito Banos-Pinero","orcid":null,"position":63,"is_corresponding":false},{"id":1219149,"name":"Maria A. Slack","orcid":null,"position":64,"is_corresponding":false},{"id":385010,"name":"Giampaolo Trivellin","orcid":"0000-0003-2384-4153","position":65,"is_corresponding":false},{"id":1218578,"name":"Benoît Mazel","orcid":"0000-0002-1788-1495","position":66,"is_corresponding":false},{"id":1218579,"name":"Maarja Soomann","orcid":"0000-0002-2237-5327","position":67,"is_corresponding":false},{"id":1218580,"name":"Samuel T. Li","orcid":"0000-0002-8020-8367","position":68,"is_corresponding":false},{"id":452824,"name":"Val J. Watts","orcid":"0000-0003-1581-2936","position":69,"is_corresponding":false},{"id":287856,"name":"Constantine A. Stratakis","orcid":"0000-0002-4058-5520","position":70,"is_corresponding":false},{"id":1218581,"name":"Maria F. Rodriguez-Quevedo","orcid":"0009-0001-8668-5113","position":71,"is_corresponding":false},{"id":469166,"name":"Ange‐Line Bruel","orcid":"0000-0002-0526-465X","position":72,"is_corresponding":false},{"id":1218582,"name":"Marita Lipsanen‐Nyman","orcid":"0000-0003-4959-2310","position":73,"is_corresponding":false},{"id":1218583,"name":"Paul Saultier","orcid":"0000-0002-6327-0898","position":74,"is_corresponding":false},{"id":562774,"name":"Rashmi Jain","orcid":"0000-0001-6819-847X","position":75,"is_corresponding":false},{"id":501408,"name":"Daphné Lehalle","orcid":"0000-0002-2193-8685","position":76,"is_corresponding":false},{"id":1218584,"name":"Daniel Torres","orcid":"0000-0003-1256-5829","position":77,"is_corresponding":false},{"id":260224,"name":"Kathleen E. Sullivan","orcid":"0000-0003-4018-1646","position":78,"is_corresponding":false},{"id":841405,"name":"S. Barbarot","orcid":"0000-0002-6629-9100","position":79,"is_corresponding":false},{"id":1011502,"name":"Axel Neu","orcid":"0000-0001-7045-7194","position":80,"is_corresponding":false},{"id":469184,"name":"Yannis Duffourd","orcid":"0000-0003-4372-4976","position":81,"is_corresponding":false},{"id":95754,"name":"Morgan N Similuk","orcid":"0000-0002-0403-2689","position":82,"is_corresponding":false},{"id":274075,"name":"Kirsty McWalter","orcid":"0000-0002-1654-9036","position":83,"is_corresponding":false},{"id":1218585,"name":"Pierre Blanc","orcid":"0009-0003-8965-7171","position":84,"is_corresponding":false},{"id":242563,"name":"Stéphane Bezieau","orcid":"0000-0003-0095-1319","position":85,"is_corresponding":false},{"id":430212,"name":"Tian Jin","orcid":"0000-0003-4815-0668","position":86,"is_corresponding":false},{"id":11554,"name":"Raif S. Geha","orcid":"0000-0002-6019-3751","position":87,"is_corresponding":false},{"id":57373,"name":"Jean-Laurent Casanova","orcid":"0000-0002-7782-4169","position":88,"is_corresponding":false},{"id":449956,"name":"Outi Mäkitie","orcid":"0000-0002-4547-001X","position":89,"is_corresponding":false},{"id":302171,"name":"Christian Kubisch","orcid":"0000-0003-4220-0978","position":90,"is_corresponding":false},{"id":325747,"name":"Patrick Edery","orcid":"0000-0001-8976-5832","position":91,"is_corresponding":false},{"id":230646,"name":"John Christodoulou","orcid":"0000-0002-8431-0641","position":92,"is_corresponding":false},{"id":228444,"name":"Ronald N. Germain","orcid":"0000-0003-1495-9143","position":93,"is_corresponding":false},{"id":656807,"name":"Christopher C. Goodnow","orcid":"0000-0001-5296-6155","position":94,"is_corresponding":false},{"id":353505,"name":"Thomas P. Sakmar","orcid":"0000-0002-2836-8953","position":95,"is_corresponding":false},{"id":290939,"name":"Daniel D. Billadeau","orcid":"0000-0002-2296-9547","position":96,"is_corresponding":false},{"id":242577,"name":"Sébastien Küry","orcid":"0000-0001-5497-0465","position":97,"is_corresponding":false},{"id":780207,"name":"Vladimir L. Katanaev","orcid":"0000-0002-7909-5617","position":98,"is_corresponding":false},{"id":104143,"name":"Yu Zhang","orcid":"0000-0002-6904-0372","position":99,"is_corresponding":false},{"id":426522,"name":"Hyoungjun Ham","orcid":"0000-0002-8669-6875","position":0,"is_corresponding":true}],"reference_count":101,"raw_metadata":null,"created_at":"2026-07-19T01:57:56.814994Z","pmid":"39298586","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}