GATA2 deficiency is a grouping of several disorders caused by common defect, namely, familial or sporadic inactivating mutations in one of the two parental GATA2 genes.
The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells.
In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ (e.g. lung) failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia.
[1][2] The various presentations of GATA2 deficiency include: 1) Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell, Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC or MonoMAC/DCML); 2) Emberger syndrome; 3) familial myelodysplastic syndrome/acute myeloid leukemia (i.e. familial MDS/AML); 3) chronic myelomonocytic leukemia (i.e. CMML); and 4) other anomalies such as aplastic anemia, chronic neutropenia, and wide-ranging immunological defects.
[2] The presentations of GATA2 deficiency commonly fall into various categories with MonoMAC and Emberger syndrome in the past and sometimes even currently being considered as separate entities.
These presentations typically occur alongside of or are followed by hematologic abnormalities including but often only after many years or decades seriously life-threatening myelodysplastic syndrome and/or acute myeloid leukemia.
[13] A small percentage of individuals with familial or sporadic GATA2 deficiency present in their childhood with asymptomatic mild neutropenia but no other discernible hematological abnormalities except perhaps monocytopenia and macrocytosis, i.e. enlarged red blood cells.
Rare individuals with inactivating GATA2 mutations may never develop symptoms, i.e. the disorder has a very high but nonetheless incomplete degree of penetrance.
[17] The many signs and symptoms that are the direct or indirect consequences of GATA2 deficiency organized based on the types of involvement are:[1][16][18][8][5][6] The GATA2 transcription factor contains two zinc finger (i.e. ZnF) motifs.
For example, displacement of GATA2 bond to this sequence by the GATA1 transcription factor appears important for the normal development of some types of hematological stem cells.
For example, in hematological stem cells, GATA2 transcription factor itself binds to one of these sites and in doing so is part of functionally important positive feedback autoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production of Interleukin 1 beta and CXCL2 which act indirectly to simulate GATA2 expression.
The human gene is also expressed in endothelium, some non-hematological stem cells, the central nervous system, and, to lesser extents, prostate, endometrium, and certain cancerous tissues.
[26] The roles, if any, of these karyotypes and somatic mutations on the development, types of presentation, and progression of GATA2 deficiency are unclear and require further study.
[1][2][19] Deletion of both Gata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in the formation of mature blood cells.
In consequence, GATA2 deficient individuals may exhibit the clinically significant disorders of chronic neutropenia, aplastic anemia, bone marrow failure, or the myelodysplastic syndrome.
Immune system deterioration would also appear responsible for the development of the pathological autoimmune reactions which affected individuals may mount against their own tissues.
[20][16][18] The GATA2 transcription factor contributes to controlling the expression of two genes, PROX1 and FOXC2, which are required for the proper development of the lymphatic system, particularly lymph vessel valves.
It is proposed that GATA2 deficiency causes a failure to develop competent valves and/or vessels in the lymphatic system and thereby leads to lymphedema.
[2] GATA2 deficiency-induced abnormalities in the lymphatic system are also proposed to be responsible for a failure in generating the perilymphatic space around the inner ear's semicircular canals, which in turn underlies the development of sensorineural hearing loss in GATA2 deficient individuals, particularly those diagnosed with the Emberger syndrome.
[7][29] The various interventions recommended for GATA2 deficiency fall into three categories: family counseling, prevention of the disease's many complications, and bone marrow transplantation in an effort to restore GATA2-sufficient stem cells.
[15][31] Standard methods are recommended for the prevention of deep vein thrombosis and/or the embolism that occur in lymphedema of the lower extremities and for the blood hypercoagulability state complicating GATA2 insufficiency presentations such as the Emberger syndrome.
While it takes up to 3.5 years for this regiment to fully re-institute good immune function, it significantly reduces susceptibility to infections and infection-induced tumor formation.
[19][15][9] Many reports on the recommended treatment of GATA2 deficiency follow an NIH clinical trial termed "A Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant regimen for Patients With GATA2 Mutations".
This trial used a regimen of medication (cyclophosphamide, fludarabine) and total body irradiation conditioning followed by allogenic hematopoietic Stem Cell Transplant on 10 patients.
[32] An NIH intervention study is in the process of recruiting and treating 144 individuals with GATA2 deficiency to determine the success of a treatment regimen consisting of medication (fludarabine, busulfan, cyclophosphamide) and total body irradiation conditioning followed by allogenic hematopoietic stem cell transplantation.
Subsequently, numerous studies discovered that a significant percentage of many other well-known hematological, immunological, autoimmune, and infectious diseases were associated with, and apparently due to, inactivating mutations in the GATA2 gene.