{"doi":"10.1101/2024.05.17.24307356","title":"Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation","abstract":"Abstract IKKα, encoded by CHUK , is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα’s role in canonical NF-κB target gene expression in human.","journal":"medRxiv","year":2024,"id":490960,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9662,"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":1290802,"name":"Boris Sorin","orcid":"0000-0002-3443-9201","position":1,"is_corresponding":false},{"id":1290803,"name":"Charline Courteille","orcid":"0009-0000-7485-9932","position":2,"is_corresponding":false},{"id":1291319,"name":"Duong Ho‐Nhat","orcid":null,"position":3,"is_corresponding":false},{"id":618891,"name":"Tom Le Voyer","orcid":"0000-0002-7253-3135","position":4,"is_corresponding":false},{"id":1290804,"name":"J Debray","orcid":"0000-0001-6082-1247","position":5,"is_corresponding":false},{"id":1072739,"name":"Marie‐Claude Stolzenberg","orcid":"0000-0001-8026-0360","position":6,"is_corresponding":false},{"id":1290805,"name":"Olivier Pellé","orcid":"0000-0002-0163-6487","position":7,"is_corresponding":false},{"id":1291321,"name":"Thomas Becquard","orcid":null,"position":8,"is_corresponding":false},{"id":1117743,"name":"María Rodrigo Riestra","orcid":null,"position":9,"is_corresponding":false},{"id":642456,"name":"Laureline Berteloot","orcid":"0000-0001-9681-3142","position":10,"is_corresponding":false},{"id":104177,"name":"Mélanie Migaud","orcid":"0000-0003-3062-1214","position":11,"is_corresponding":false},{"id":1072736,"name":"Laure Delage","orcid":"0000-0002-5235-9985","position":12,"is_corresponding":false},{"id":1290806,"name":"Marie Jeanpierre","orcid":"0009-0009-2758-6180","position":13,"is_corresponding":false},{"id":1290807,"name":"Charlotte Boussard","orcid":"0000-0002-1237-8321","position":14,"is_corresponding":false},{"id":1073223,"name":"Camille Brunaud","orcid":null,"position":15,"is_corresponding":false},{"id":1047672,"name":"Aude Magérus","orcid":"0000-0001-7365-699X","position":16,"is_corresponding":false},{"id":1290808,"name":"V. 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