GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation

摘要: Germline GATA2 mutations have been identified as the cause of familial syndromes with immunodeficiency and predisposition to myeloid malignancies. appear loss function mutated allele leading haploinsufficiency; however, this postulate has not experimentally validated basis these syndromes. We hypothesized that are translated into abnormal proteins could affect transcription GATA2, triggering deficiency. Chromatin immunoprecipitation luciferase assays showed human protein activates its own through a specific region located at -2.4 kb, whereas p.Thr354Met, p.Thr355del, p.Arg396Gln germline impair promoter activation. Accordingly, expression was decreased ∼58% in patient p.Arg396Gln, compared controls. is second most common mutation syndromes, no previous functional analyses performed. therefore analyzed p.Arg396Gln. Our data show loss-of-function affecting DNA-binding ability and, consequence, it fails maintain immature characteristics hematopoietic stem progenitor cells, which result defects cell compartment. In conclusion, we binds promoter, activating transcription, aforementioned GATA2. results indicate they can other target genes, partially explain variability symptoms diseases. Moreover, mutation, unable retain phenotype cells where expressed.