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

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 (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

SUBMITTER: Hasegawa A 

PROVIDER: S-EPMC9018821 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature