Human GATA2 mutations and hematologic disease: how many paths to pathogenesis?

Abstract

The surge of human genetic information, enabled by increasingly facile and economically feasible genomic technologies, has accelerated discoveries on the relationship of germline genetic variation to hematologic diseases. For example, germline variation in GATA2, encoding a vital transcriptional regulator of multilineage hematopoiesis, creates a predisposition to bone marrow failure and acute myeloid leukemia termed GATA2 deficiency syndrome. More than 300 GATA2 variants representing missense, truncating, and noncoding enhancer mutations have been documented. Although these variants can diminish GATA2 expression and/or function, the functional ramifications of many variants are unknown. Studies using genetic rescue and knockin mouse systems have established that GATA2 mutations differentially affect molecular processes in distinct target genes and within a single target cell. Considering that target genes for a transcription factor can differ in sensitivity to altered levels of the factor, and transcriptional mechanisms are often cell type specific, the context-dependent consequences of GATA2 mutations in experimental systems portend the complex phenotypes and interindividual variation of GATA2 deficiency syndrome. This review documents GATA2 human genetics and the state of efforts to traverse from physiological insights to pathogenic mechanisms.

Figure 1.

Human GATA2 coding mutations. GATA2 mutations that are designated “pathogenic,” “likely pathogenic,” and “uncertain significance” and their corresponding protein sequences. Top, GATA2 protein sequence depicting mutations external to the zinc finger domain. Bottom, enlargement of GATA2 zinc finger domain illustrating amino acids affected by mutations. Reported mutations are indicated in pink. N-ZF, N-finger; INT-ZF, inter-zinc finger spacer; C-ZF, C-finger. N- and C-fingers are also referred to as Zf1 and Zf2, respectively.

Figure 2.

Relationship of human clinical genetic mutations and GATA2 posttranslational modification sites. (A) Multisite GATA2 phosphorylation model. Extracellular signal–regulated kinase (ERK)/p38α docks on the GATA2 DEF motif, S192 is phosphorylated, and other serine residues (S73, S119, S290, and S340) are phosphorylated subsequently. (B) Top, GATA2 protein structure. N- and C-zinc fingers, DEF motif, phosphorylated residues, and acetylated residues are indicated. Bottom, amino acid sequence from 165 aa to 200 aa of GATA2 protein. Phosphorylated residues, DEF motif, and mutations reported by ClinVar/ClinGen are indicated.