{"doi":"10.70962/jhi.20250097","title":"<i>ORAI1</i> mutation with mixed loss- and gain-of-function properties causes immunodeficiency and HLH","abstract":"Loss-of-function mutations of ORAI1 suppress store-operated Ca2+ entry (SOCE) and cause an immunodeficiency disorder called Ca2+ release–activated Ca2+ channelopathy. Here, we report an infant patient who is compound-heterozygous for p.His134Pro and p.Leu194Pro mutations in ORAI1 and whose T cells have strongly reduced SOCE. Whereas the p.Leu194Pro mutant ORAI1 protein is not expressed at the plasma membrane, the p.His134Pro mutation results in a constitutively open channel that is unresponsive to activation by stromal interaction molecule 1. The patient suffered from a severe form of combined immunodeficiency, hemophagocytic lymphohistiocytosis, and fatal chronic cytomegalovirus infection. His immunodeficiency was characterized by an altered composition of T and NK cell compartments, impaired stimulation-induced cytokine production and signs of CD4+ T cell and NK cell activation, but attenuated CD8+ T effector memory cell function. Our findings demonstrate that small constitutive SOCE through a mutant ORAI1 channel is not sufficient to provide immunity to viral infection.","journal":"Journal of Human Immunity","year":2025,"id":579596,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":374082,"name":"Priscilla S.-W. Yeung","orcid":"0000-0001-5400-8639","position":1,"is_corresponding":false},{"id":244371,"name":"Sascha Kahlfuß","orcid":"0000-0001-8813-1061","position":2,"is_corresponding":false},{"id":883725,"name":"Catherine L. Lai","orcid":"0000-0002-4076-0464","position":3,"is_corresponding":false},{"id":1002353,"name":"Maxwell McDermott","orcid":"0009-0005-9503-0556","position":4,"is_corresponding":false},{"id":1490165,"name":"Devisha Patel","orcid":"0009-0009-0295-1049","position":5,"is_corresponding":false},{"id":1490166,"name":"Jun Yang","orcid":"0009-0009-1159-0898","position":6,"is_corresponding":false},{"id":815116,"name":"Yin‐Hu Wang","orcid":"0000-0002-3637-8852","position":7,"is_corresponding":false},{"id":266518,"name":"Li Zhong","orcid":"0000-0003-3094-4806","position":8,"is_corresponding":false},{"id":513481,"name":"Peter Hsu","orcid":"0000-0003-4620-073X","position":9,"is_corresponding":false},{"id":353487,"name":"Murali Prakriya","orcid":"0000-0003-0781-4480","position":10,"is_corresponding":false},{"id":244372,"name":"Stefan Feske","orcid":"0000-0001-5431-8178","position":11,"is_corresponding":false},{"id":325423,"name":"Lucile Noyer","orcid":"0000-0002-1369-684X","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:58:34.718602Z","pmid":"41200103","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":[]}