Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature.

Publication Type:

Journal Article


Blood, Volume 119, Issue 5, p.1283-1291 (2012)


2012, Adolescent, Adult, Animals, Cells, Cultured, Center-Authored Paper, Clinical Research Division, Female, GATA2 Transcription Factor, Germ-Line Mutation, Humans, Infant, Newborn, January 2012, Leukemia, Myeloid, Acute, Lymphangiogenesis, Lymphatic Vessels, Lymphedema, Male, MICE, Mice, Inbred C57BL, Mice, Transgenic, Monocytes, Myelodysplastic Syndromes, Syndrome, Young Adult


Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML), "MonoMAC" syndrome and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense mutation in GATA2 (p.Thr354Met), one patient with MDS/AML carrying a frameshift mutation in GATA2 (p.Leu332Thrfs*53), another individual with MDS harboring a GATA2 splice site mutation, and three patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, two patients with GATA2 deletions and one with a frameshift mutation who have MDS/AML or "MonoMAC" syndrome also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in the leaflets of lymphatic vessel valves, and that GATA2 controls the expression of genes that play key roles in programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss-of-function (LOF) of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development, particularly in controlling valve development and/or function.