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

Amy P. Hsu, Elizabeth P. Sampaio, Javed Khan, Katherine R. Calvo, Jacob E. Lemieux, Smita Y. Patel, David M. Frucht, Donald C. Vinh, Roger D. Auth, Alexandra F. Freeman, Kenneth N. Olivier, Gulbu Uzel, Christa S. Zerbe, Christine Spalding, Stefania Pittaluga, Mark Raffeld, Douglas B. Kuhns, Li Ding, Michelle L. Paulson, Beatriz E. Marciano, Juan C. Gea-Banacloche, Jordan S. Orange, Jennifer Cuellar-Rodriguez, Dennis D. Hickstein, Steven M. Holland

Abstract

The syndrome of monocytopenia, B and NK cell lymphopenia and mycobacterial, fungal and viral infections (MonoMAC) 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 frameshifts 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.

  • Submitted May 24, 2011.
  • Accepted May 31, 2011.