Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks

J Clin Invest. 2023 Apr 3;133(7):e162685. doi: 10.1172/JCI162685.


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.

Keywords: Genetic variation; Genetics; Hematology; Signal transduction; Transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • GATA2 Deficiency* / genetics
  • GATA2 Transcription Factor / genetics
  • GATA2 Transcription Factor / metabolism
  • Gene Expression
  • Granulocyte-Macrophage Colony-Stimulating Factor*
  • Hematopoiesis / genetics
  • Humans
  • Interleukin-6 / genetics
  • Zinc Fingers / genetics


  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Interleukin-6
  • GATA2 Transcription Factor
  • GATA2 protein, human