title: 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.
abstract: Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), "MonoMAC" syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 deletions and one with a frameshift mutation 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 lymphatic vessel valves and that GATA2 controls the expression of genes important for 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 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.
authors.affiliation: Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, 5000 SA, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Kazenwadel
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Secker
authors.forename: Yajuan J
authors.initials: YJ
authors.lastname: Liu
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wildin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cuellar-Rodriguez
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Sarah
authors.initials: S
authors.lastname: Dyack
authors.forename: Conrad V
authors.initials: CV
authors.lastname: Fernandez
authors.forename: Chan-Eng
authors.initials: CE
authors.lastname: Chong
authors.forename: Milena
authors.initials: M
authors.lastname: Babic
authors.forename: Peter G
authors.initials: PG
authors.lastname: Bardy
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Zhang
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Hahn
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Harvey
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018095:Germ-Line Mutation / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D042583:Lymphangiogenesis / Q000235:genetics; D042601:Lymphatic Vessels / Q000378:metabolism*; D008209:Lymphedema / Q000151:congenital* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human