{"doi":"10.1084/jem.20202592","title":"Human <i>STAT3</i> variants underlie autosomal dominant hyper-IgE syndrome by negative dominance","abstract":"Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.","journal":"The Journal of Experimental Medicine","year":2021,"id":154876,"datarank":0.6190701577567639,"base_score":4.127134385045092,"endowment":4.127134385045092,"self_citation_contribution":0.6190701577567639,"citation_network_contribution":0.0,"self_endowment_contribution":0.6190701577567639,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":61,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"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":655778,"name":"Joëlle Khourieh","orcid":"0000-0002-5953-2883","position":1,"is_corresponding":false},{"id":104484,"name":"Peng Zhang","orcid":"0000-0002-6129-567X","position":2,"is_corresponding":false},{"id":104485,"name":"Franck Rapaport","orcid":"0000-0001-6553-2110","position":3,"is_corresponding":false},{"id":104167,"name":"András N. 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