Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding

• Published in: Communications biology Vol. 5; no. 1; p. 376
• Main Authors: Hasegawa, Atsushi, Hayasaka, Yuki, Morita, Masanobu, Takenaka, Yuta, Hosaka, Yuna, Hirano, Ikuo, Yamamoto, Masayuki, Shimizu, Ritsuko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.04.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 45/70; 631/136/1425; 631/136/232/1997; 64/60; Amino acid substitution; Animals; Biology; Biomedical and Life Sciences; Dendritic cells; GATA2 Transcription Factor - genetics; Heterozygote; Humans; Life Sciences; Mice; Molecular modelling; Monocytes; Monocytes - metabolism; Mutation; Phenotype; Phenotypes; Protein Binding; Receptors, Chimeric Antigen - genetics; Regulatory sequences; Tryptophan
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03316-w

Accumulating lines of clinical evidence support the emerging hypothesis that loss-of-function mutations of GATA2 cause inherited hematopoietic diseases, including Emberger syndrome; dendritic cell, monocyte B and NK lymphoid (DCML) deficiency; and MonoMAC syndrome. Here, we show that mice heterozygous for an arginine-to-tryptophan substitution mutation in GATA2 ( G2 R398W/+ ), which was found in a patient with DCML deficiency, substantially phenocopy human DCML deficiency. Mice heterozygous for the GATA2-null mutation ( G2 -/+ ) do not show such phenotypes. The G2 R398W protein possesses a decreased DNA-binding affinity but obstructs the function of coexpressed wild-type GATA2 through specific cis -regulatory regions, which contain two GATA motifs in direct-repeat arrangements. In contrast, G2 R398W is innocuous in mice containing single GATA motifs. We conclude that the dominant-negative effect of mutant GATA2 on wild-type GATA2 through specific enhancer/silencer of GATA2 target genes perturbs the GATA2 transcriptional network, leading to the development of the DCML-like phenotype. The present mouse model provides an avenue for the understanding of molecular mechanisms underlying the pathogenesis of GATA2-related hematopoietic diseases. DCML deficiency is a disorder marked by loss of multiple immune cell types. Mutations that affect a single allele of the GATA2 transcription factor may lead to DCML by interfering with normal GATA2 binding, altering expression of important immune cell pathways.