{"doi":"10.7554/elife.72559","title":"Biallelic mutations in calcium release activated channel regulator 2A (CRACR2A) cause a primary immunodeficiency disorder","abstract":"CRAC channel regulator 2 A (CRACR2A) is a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca 2+ -NFAT and JNK-AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies, however, to date no patient with damaging variants in CRACR2A has been identified. In this study, we describe a patient harboring biallelic variants in CRACR2A [paternal allele c.834 gaG> gaT (p.E278D) and maternal alelle c.430 Aga > Gga (p.R144G) c.898 Gag> Tag (p.E300*)], the gene encoding CRACR2A. The 33-year-old patient of East-Asian origin exhibited late onset combined immunodeficiency characterised by recurrent chest infections, panhypogammaglobulinemia and CD4+ T cell lymphopenia. In vitro exposure of patient B cells to a T-dependent stimulus resulted in normal generation of antibody-secreting cells, however the patient’s T cells showed pronounced reduction in CRACR2A protein levels and reduced proximal TCR signaling, including dampened SOCE and reduced JNK phosphorylation, that contributed to a defect in proliferation and cytokine production. Expression of individual allelic mutants in CRACR2A-deleted T cells showed that the CRACR2A E278D mutant did not affect JNK phosphorylation, but impaired SOCE which resulted in reduced cytokine production. The truncated double mutant CRACR2A R144G/E300* showed a pronounced defect in JNK phosphorylation as well as SOCE and strong impairment in cytokine production. Thus, we have identified variants in CRACR2A that led to late-stage combined immunodeficiency characterized by loss of function in T cells.","journal":"eLife","year":2021,"id":176913,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":721171,"name":"Laura Rice","orcid":null,"position":1,"is_corresponding":false},{"id":720337,"name":"Jennifer Shrimpton","orcid":"0000-0002-6346-6516","position":2,"is_corresponding":false},{"id":720338,"name":"Dylan Lawless","orcid":"0000-0001-8496-3725","position":3,"is_corresponding":false},{"id":720339,"name":"Kieran Walker","orcid":"0000-0002-6694-2979","position":4,"is_corresponding":false},{"id":721172,"name":"Clive Carter","orcid":null,"position":5,"is_corresponding":false},{"id":721173,"name":"Lynn McKeown","orcid":null,"position":6,"is_corresponding":false},{"id":721174,"name":"Rashida Anwar","orcid":null,"position":7,"is_corresponding":false},{"id":721175,"name":"Gina M Doody","orcid":null,"position":8,"is_corresponding":false},{"id":378709,"name":"Sonal Srikanth","orcid":"0000-0002-3034-095X","position":9,"is_corresponding":false},{"id":374505,"name":"Yousang Gwack","orcid":"0000-0002-2821-9245","position":10,"is_corresponding":false},{"id":218264,"name":"Sinisa Savic","orcid":"0000-0001-7910-0554","position":11,"is_corresponding":false},{"id":709971,"name":"Beibei Wu","orcid":"0000-0002-0784-0745","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-18T23:47:28.018172Z","pmid":"34908525","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":[]}