Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome

Abstract

The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.

Figure 1

GATA2 gene. (A) Genomic organization of GATA2 showing 2 5′-untranslated and 5 coding exons. Wider boxes represent coding regions. Insertion/deletion mutations predicted to result in null alleles are shown above. (B) Protein domains of GATA2, showing N- and C-terminal zinc fingers (ZF-1, ZF-2) and nuclear localization signal (N). (C) Missense and in-frame deletion mutations identified within ZF-2. Superscript numerals indicate the number of independent mutations.