1 Nature Genetics 2011 Vol: 43(10):929-931. DOI: 10.1038/ng.923

Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)

Sahar Mansour and colleagues report alterations in the transcription factor GATA2 in eight pedigrees with Emberger disorder, which is characterized by primary lymphedema and predispositon to acute myeloid leukemia. Most of the heterozygous variants lead to frameshift mutations and premature termination of GATA2.

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Figures
Figure 1: Clinical and genetic findings in Emberger syndrome. (a) Bilateral lower limb lymphedema in subject Emb-01 III-1. (b) Four limb lymphoscintigraphy performed in subject Emb-01 III-1 showing no demonstrable main tract filling of the lower limbs at 2 h. (c) Location of the eight identified mutations with respect to the genomic organization of the GATA2 gene (above) and GATA2 protein domain structure (below).
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References
  1. Mansour, S. Am. J. Med. Genet. 152A, 2287-2296 (2010) .
    • . . . The co-occurrence of primary lymphedema with myelodysplasia progressing to acute myeloid leukemia (AML), termed Emberger syndrome (MIM614038), has been reported as a sporadic disorder but has also been observed in a limited number of kindreds1 . . .
    • . . . Within one family (Emb-01), this variability ranged from hydrops fetalis evolving to severe bilateral lower limb lymphedema (Fig. 1a,b) with genital involvement and development of AML at 11 years of age (individual Emb-01 III-1) to an obligate carrier (her father, Emb-01 II-1) with minimal edema and a normal lymphocyte count but a low CD4/CD8 ratio (the case reports of Emb-01 are presented as case 1 in ref. 1) . . .
  2. Song, W.-J. Nat. Genet. 23, 166-175 (1999) .
    • . . . Germline RUNX1 haploinsufficiency underlies an autosomal dominant familial platelet disorder with propensity to myeloid malignancy (MIM601399)2, and inherited mutations in CEBPA (the gene encoding the transcription factor CCAAT/enhancer binding protein α (C/EBPα)) have also been identified in a small number of families with AML3 . . .
  3. Smith, M.L. N. Engl. J. Med. 351, 2403-2407 (2004) .
    • . . . Germline RUNX1 haploinsufficiency underlies an autosomal dominant familial platelet disorder with propensity to myeloid malignancy (MIM601399)2, and inherited mutations in CEBPA (the gene encoding the transcription factor CCAAT/enhancer binding protein α (C/EBPα)) have also been identified in a small number of families with AML3 . . .
  4. Preudhomme, C. Blood 96, 2862-2869 (2000) .
    • . . . Both RUNX1 and C/EBPα are transcription factors central to the development of normal hematopoiesis, and somatic mutations in both genes have been identified in sporadic AML4, 5 . . .
  5. Pabst, T. Nat. Genet. 27, 263-270 (2001) .
    • . . . Both RUNX1 and C/EBPα are transcription factors central to the development of normal hematopoiesis, and somatic mutations in both genes have been identified in sporadic AML4, 5 . . .
  6. Tsai, F.-Y. Nature 371, 221-226 (1994) .
    • . . . Homozygous Gata2 knockout mice die during mid gestation from severe anemia, with levels of myeloid-erythroid progenitor cells being reduced in comparison to wild-type controls6 . . .
  7. Rodrigues, N.P. Blood 112, 4862-4873 (2008) .
    • . . . Analysis of heterozygous mice haploinsufficient for Gata2 revealed disruption of hematopoietic stem cell homeostasis within the granular macrophage progenitor compartment, which has previously been shown to be vulnerable to leukemic transformation7. . . .
  8. Zheng, R.; Blobel, G.A. Genes Cancer 1, 1178-1188 (2010) .
    • . . . GATA transcription factors have previously been implicated in human cancers (reviewed in ref. 8) . . .
  9. Zhang, S.-J. Proc. Natl. Acad. Sci. USA 105, 2076-2081 (2008) .
    • . . . Indeed, somatic mutation of GATA2 has been identified in samples from individuals with chronic myeloid leukemia undergoing blast transformation9 . . .
  10. Callier, P. Am. J. Med. Genet. 149A, 1323-1326 (2009) .
    • . . . The germline defects in GATA2 underlying an inherited predisposition to AML, findings that are supported by the recent identification of a microdeletion at 3q21, encompassing 36 genes, including GATA2, in an individual with multiple congenital abnormalities and development of myelodysplasia with monosomy 7 at the age of 11 years10 . . .
  11. Tong, Q. Mol. Cell. Biol. 25, 706-715 (2005) .
    • . . . Also of interest and relevant to our findings, GATA2 has been shown to form protein complexes with C/EBPα11, implicating mutation of either of the genes that encode for these transcription factors in inherited predisposition to AML. . . .
  12. Khandekar, M. Development 134, 1703-1712 (2007) .
    • . . . GATA2 is known to be expressed in lymphatic, vascular and endocardial endothelial cells12 . . .
  13. Haugas, M. Dev. Dyn. 239, 2452-2469 (2010) .
    • . . . We also note the described function of Gata2 in vestibular morphogenesis and growth of the semicircular canals13; the relationship of these findings with the development of sensorineural deafness in 3 of the 14 mutation-carrying mice requires further investigation. . . .
  14. Hsu, A.P. Blood , .
    • . . . Heterozygous mutations in GATA2 have recently been identified in individuals with monocytopenia and mycobacterial infection (MonoMAC) syndrome14 and also in individuals with dendritic cell, monocyte, B and natural killer lymphoid deficiency15. . . .
  15. Dickinson, R.E. Blood , .
    • . . . Heterozygous mutations in GATA2 have recently been identified in individuals with monocytopenia and mycobacterial infection (MonoMAC) syndrome14 and also in individuals with dendritic cell, monocyte, B and natural killer lymphoid deficiency15. . . .
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