{"doi":"10.3389/flupu.2023.1186641","title":"Lupus-associated NCF2 variant p.R395W in the NADPH oxidase 2 complex results in a reduced production of reactive oxygen species by myeloid cells","abstract":"The leukocyte NADPH oxidase 2 (NOX2) generates superoxide, and derivative reactive oxygen species play important roles in both host defense and immunoregulation. The rs13306575 genetic variant, resulting in an Arginine395→Tryptophan (R395W) substitution in the NOX2 NCF2 subunit, is associated with an increased risk of lupus in patients of Hispanic-American or of Korean ancestry. Arginine395 resides within the NCF2 PB1 domain and participates in a constitutive high-affinity interaction with the NOX2 NCF4 subunit to stabilize their expression. However, whether this variant impacts NCF2 function and NOX2 activity is unknown. To answer this question, mice expressing NCF2-R395W were generated using CRISPR/Cas9. NCF2 and NCF4 expression were reduced by twofold in neutrophils, macrophages, and dendritic cells homozygous for NCF2-R395W. Moreover, following stimulation with soluble or particulate stimuli, reactive oxygen species production at the plasma membrane and within cells was reduced in all three myeloid lineages expressing NCF2-R395W. Additional studies on Ncf2 +/− mice, which have a reduced expression of wild-type NCF2 but not of NCF4, suggest that the reduced expression of both NCF2 and NCF4 contributes to the diminished NOX2 activity in NCF2-R395 mice. These results establish that the lupus-associated rs13306575 p.R395W allele is a functional hypomorph. The findings add to growing evidence implicating deficient NOX2 activity in the pathogenesis of lupus.","journal":"Frontiers in Lupus","year":2023,"id":376968,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":751402,"name":"Dae‐Goon Yoo","orcid":"0000-0002-6330-9975","position":1,"is_corresponding":false},{"id":899842,"name":"Rachel A. Idol","orcid":"0000-0002-7043-6630","position":2,"is_corresponding":false},{"id":383873,"name":"Emilia Alina Barbu","orcid":"0000-0002-3511-4679","position":3,"is_corresponding":false},{"id":338093,"name":"Chaim O. Jacob","orcid":null,"position":4,"is_corresponding":false},{"id":280633,"name":"Mary C. Dinauer","orcid":"0000-0002-7796-2908","position":5,"is_corresponding":false},{"id":688000,"name":"Zhimin Song","orcid":"0000-0001-7977-2158","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:16:32.368674Z","pmid":null,"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":[]}