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- Title
Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding.
- Authors
Hasegawa, Atsushi; Hayasaka, Yuki; Morita, Masanobu; Takenaka, Yuta; Hosaka, Yuna; Hirano, Ikuo; Yamamoto, Masayuki; Shimizu, Ritsuko
- Abstract
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 (G2R398W/+), 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 G2R398W 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, G2R398W 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.
- Subjects
GENETIC variation; PROTEIN binding; GENE regulatory networks; MICE; TRANSCRIPTION factors; GENE enhancers; DENDRITIC cells; CIS-regulatory elements (Genetics)
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03316-w