{"doi":"10.1172/jci162685","title":"Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks","abstract":"Although certain human genetic variants are conspicuously loss of function, decoding the impact of many variants is challenging. Previously, we described a patient with leukemia predisposition syndrome (GATA2 deficiency) with a germline GATA2 variant that inserts 9 amino acids between the 2 zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide. Despite nuclear localization, 9aa-Ins was severely defective in occupying and remodeling chromatin and regulating transcription. Variation of the inter-zinc finger spacer length revealed that insertions were more deleterious to activation than repression. GATA2 deficiency generated a lineage-diverting gene expression program and a hematopoiesis-disrupting signaling network in progenitors with reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) and elevated IL-6 signaling. As insufficient GM-CSF signaling caused pulmonary alveolar proteinosis and excessive IL-6 signaling promoted bone marrow failure and GATA2 deficiency patient phenotypes, these results provide insight into mechanisms underlying GATA2-linked pathologies.","journal":"Journal of Clinical Investigation","year":2023,"id":338077,"datarank":0.4493598410330987,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.0,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"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":459569,"name":"Siqi Shen","orcid":"0000-0003-1661-1247","position":1,"is_corresponding":false},{"id":325218,"name":"Giovanni A. Botten","orcid":"0000-0001-8054-8030","position":2,"is_corresponding":false},{"id":1007460,"name":"Thomas Olender","orcid":"0000-0003-3617-5163","position":3,"is_corresponding":false},{"id":438088,"name":"Koichi R. Katsumura","orcid":"0000-0002-1523-0533","position":4,"is_corresponding":false},{"id":459567,"name":"Kirby D. Johnson","orcid":"0000-0003-0236-7482","position":5,"is_corresponding":false},{"id":571351,"name":"Alexandra A. Soukup","orcid":"0000-0002-4149-2393","position":6,"is_corresponding":false},{"id":459568,"name":"Peng Liu","orcid":"0000-0001-5655-2259","position":7,"is_corresponding":false},{"id":776235,"name":"Qingzhou Zhang","orcid":"0000-0001-9540-2624","position":8,"is_corresponding":false},{"id":1070443,"name":"Zena D. Jensvold","orcid":"0000-0002-4783-4411","position":9,"is_corresponding":false},{"id":284387,"name":"Peter W. Lewis","orcid":"0000-0002-9816-7823","position":10,"is_corresponding":false},{"id":268092,"name":"Robert A. Beagrie","orcid":"0000-0003-1076-5595","position":11,"is_corresponding":false},{"id":308197,"name":"Jason K. K. Low","orcid":"0000-0003-0862-0012","position":12,"is_corresponding":false},{"id":1070444,"name":"Lihua Yang","orcid":"0000-0003-4257-0610","position":13,"is_corresponding":false},{"id":78312,"name":"Joel P. Mackay","orcid":"0000-0001-7508-8033","position":14,"is_corresponding":false},{"id":438090,"name":"Lucy A. Godley","orcid":"0000-0003-1914-9158","position":15,"is_corresponding":false},{"id":335211,"name":"Marjorie Brand","orcid":"0000-0001-8915-8012","position":16,"is_corresponding":false},{"id":56479,"name":"Jian Xu","orcid":"0000-0003-1988-7337","position":17,"is_corresponding":false},{"id":43259,"name":"Sündüz Keleş","orcid":"0000-0001-9048-0922","position":18,"is_corresponding":false},{"id":333666,"name":"Emery H. Bresnick","orcid":"0000-0002-1151-5654","position":19,"is_corresponding":false},{"id":1070442,"name":"Mabel M. Jung","orcid":"0000-0001-7258-2888","position":0,"is_corresponding":true}],"reference_count":131,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:10:35.973121Z","pmid":"36809258","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":[]}