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
Por:
Kazenwadel J., Secker G.A., Liu Y.J., Rosenfeld J.A., Wildin R.S., Cuellar-Rodriguez J., Hsu A.P., Dyack S., Fernandez C.V., Chong C.-E., Babic M., Bardy P.G., Shimamura A., Zhang M.Y., Walsh T., Holland S.M., Hickstein D.D., Horwitz M.S., Hahn C.N., Scott H.S., Harvey N.L.
Publicada:
1 ene 2012
Resumen:
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.
Filiaciones:
Kazenwadel J.:
Division of Haematology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
Secker G.A.:
Division of Haematology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
Liu Y.J.:
Department of Pathology, University of Washington School of Medicine, Seattle, WA, United States
Rosenfeld J.A.:
Signature Genomics, PerkinElmer, Spokane, WA, United States
Wildin R.S.:
St Luke's Children's Hospital, State of Idaho Genetics Program, Department of Health and Welfare, Boise, ID, United States
Cuellar-Rodriguez J.:
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, United States
Hsu A.P.:
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, United States
Dyack S.:
Department of Pediatrics, Maritime Medical Genetics Service, Dalhousie University, Halifax, NS, Canada
Fernandez C.V.:
Departments of Pediatrics and Bioethics, IWK Health Centre, Dalhousie University, Halifax, NS, Canada
Chong C.-E.:
Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
School of Medicine, University of Adelaide, Adelaide, SA, Australia
Babic M.:
Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
Bardy P.G.:
Division of Haematology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
Shimamura A.:
Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Seattle Children's Hospital, Seattle, WA, United States
Zhang M.Y.:
Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Department of Genome Sciences, Department of Medicine, University of Washington, Seattle, WA, United States
Walsh T.:
Department of Genome Sciences, Department of Medicine, University of Washington, Seattle, WA, United States
Holland S.M.:
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, United States
Hickstein D.D.:
Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, United States
Horwitz M.S.:
Department of Pathology, University of Washington School of Medicine, Seattle, WA, United States
Hahn C.N.:
Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
School of Medicine, University of Adelaide, Adelaide, SA, Australia
Scott H.S.:
Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
School of Medicine, University of Adelaide, Adelaide, SA, Australia
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
Harvey N.L.:
Division of Haematology, Centre for Cancer Biology, SA Pathology, PO Box 14, Adelaide, SA 5000, Australia
School of Medicine, University of Adelaide, Adelaide, SA, Australia
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