LAUSR

GATA2 deficiency syndrome is an autosomal dominant disorder caused by germline mutations in the GATA2 gene, which encodes a transcription factor with two zinc fingers that is essential for hematopoiesis. There are four classes of these GATA2 mutations: truncating mutations proximal to the C-finger, C-finger missense mutations, noncoding mutations within an intron, and mutations resulting in aberrant mRNA splicing. Here, we report a novel GATA2 mutation that defines a new class of germline mutation: an in-frame insertion mutation that increases the separation of the two zinc fingers through the addition of nine amino acids. By several functional tests, this mutation was shown to be defective, establishing it as a pathogenic mutation and a new type of germline GATA2 mutation. GATA2 deficiency syndrome is a phenotypically heterogeneous autosomal dominant disorder caused by mutations in the GATA2 gene, which encodes a transcription factor essential for hematopoiesis [1]. GATA2 deficiency has a varied clinical presentation that includes congenital lymphedema, immunodeficiency, viral/fungal/bacterial infections, especially of atypical mycobacterial species, and alveolar proteinosis among others [2]. GATA2 deficiency patients, both pediatric and adult, are predisposed to bone marrow failure and have an elevated risk of developing myeloid malignancies [2]. GATA2 is a member of the GATA transcription factor family that selectively occupies GATA motifs in chromatin [3]. GATA proteins have a conserved dual zinc-finger domain, with the carboxy-terminal (C) finger mediating DNA binding [4]. Although the GATA1 amino-terminal Nfinger mediates protein interactions with its coregulator Friend of GATA1 [5], GATA2 N-finger function is not established. GATA2 establishes and maintains hematopoietic stem/progenitor cell pools [6, 7] and erythroid precursor cells [8]. Most GATA2 germline mutations reported fall into one of four categories: truncating mutations proximal to the Cfinger, C-finger missense mutations, noncoding mutations within the “+9.5” enhancer located within intron 4, and mutations resulting in aberrant mRNA splicing [9, 10]. Unlike somatic mutations that occur in the N-finger [11], most germline mutations reported are within the C-finger and reduce DNA binding in vitro [12]. Coding and enhancer mutations can reduce GATA2 activity or expression, thus potentially causing haploinsufficiency. However, as not all GATA2 disease-linked mutants lack activity in a genetic complementation assay that quantifies GATA2 activity to regulate endogenous target genes and myelo-erythroid differentiation [13], the mechanistic basis for pathogenicity is not established. Here, we report a GATA2 human disease mutation that defines a new class of germline GATA2 mutations: an inframe mutation that inserts 9 amino acids between the first and second zinc fingers (9-aa ins-mut), resulting in increased separation of the two zinc fingers. A 29-year-old These authors contributed equally: Marcela Cavalcante de Andrade Silva, Koichi R. Katsumura