the gene code for two zinc finger structural motifs, zf1 and zf2, respectively, of the gata2 transcription factor. zf1 and zf2 are critical for regulating the ability of gata2 transcription factor to stimulate its target genes. the gata2 gene has at least five separate sites which bind nuclear factors that regulate its expression. one particularly important such site is located in intron 4. this site, termed the 9.5 kb enhancer, is located 9.5 kilobases (i.e. kb) down-stream from the gene's transcript initiation site and is a critically important enhancer of the gene's expression. regulation of gata2 expression is highly complex. 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. in an example of a negative feedback circuit, the gata2 transcription factor indirectly causes activation of the g protein-coupled receptor, gpr65, which then acts, also indirectly, to repress gata2 gene expression. in a second example of negative feed-back, gata2 transcription factor stimulates the expression of the gata1 transcription factor which in turn can displace gata2 transcription factor from its gene-stimulating binding sites thereby limiting gata2's actions (see gata2 switch in "gata2 transcription factor" section). the human gata2 gene is expressed in hematological bone marrow cells at the stem cell and later progenitor cell stages of their development. increases and/or decreases in the gene's expression regulate the self-renewal, survival, and progression of these immature cells toward their final mature forms viz., erythrocytess, certain types of lymphocytes (i.e. b cells, nk cells, and t helper cells), monocytes, neutrophils, platelets, plasmacytoid dendritic cells, macrophages and mast cells. the gene is likewise critical for the formation of the lymphatic system, particularly for the development of its valves. 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. scores of different types of inactivating gata mutations have been associated with gata2 deficiency; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the gata2 transcription factor's zf1, zf2, and 9.5 kb sites. rare cases of gata2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of gata mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances. non-mutational gata2 deficiency analyses of individuals with aml have discovered many cases of gata2 deficiency in which one parental gata2 gene was not mutated but silenced by hypermethylation of its gene promoter. further studies are required to define the involvement of this hypermethylation-induced form of gata2 deficiency in other disorders as well to integrate it into the diagnostic category of gata2 deficiency. other genetic abnormalities gata2 deficiency disorders are variably associated with secondary genetic abnormalities. monosomy of chromosome 7 (i.e. lose of one of the two chromosomes 7) or deletion of the "q" (i.e. short arm) of one chromosome 7 are the most common abnormal karyotypes (i.e. abnormal chromosome number or appearance) associated with gata2 deficiency, occurring in ~41% of cases; less common abnormal karyotypes associated with the deficiency include chromosome 8 trisomy (8% of cases) and, rarely, chromosome 21 monosomy. gata2 deficiency is also associated with somatic mutations in at least three other genes viz., asxl1, setbp1, and stag2. independently of gata2 mutations and the development of gata2 deficiency, asxl1 mutations are associated with mds, aml, cmml, chronic lymphocytic leukemia, myeloproliferative neoplasm, and cancers of the breast, cervix, and liver, setbp1 mutations are associated with atypical mds, cmml, chronic myelogenous leukemia, and chronic neutrophilic leukemia, and stag2 mutations are associated with mds, aml, cmml, chronic myelogenous leukemia, and cancers of the bladder, stomach, colon, rectum, and prostate gland. 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. pathophysiology blood defects 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. inactivation of one mouse gata2 gene is neither lethal nor associated with most of the signs of human gata2 deficiency; however, these animals do show a ~50% reduction in their hematopoietic stem cells along with a reduced ability to repopulate the bone marrow of mouse recipients. the latter findings, human clinical studies, and experiments on human tissues support the conclusion that in humans both parental gata2 genes are required for sufficient numbers of hematopoietic stem cells to emerge from the hemogenic endothelium during embryogenesis and for these cells and subsequent progenitor cells to survive, self-renew, and differentiate into mature cells. as gata2 deficient individuals age, their deficiency in hematopoietic stem cells worsens, probably as a result of factors such as infections or other stresses. in consequence, the signs and symptoms of their disease appear and/or become progressively more severe. monomac-affected individuals exhibit reduced levels of common lymphoid progenitor cells (i.e. a heterogenous group of precursors to various lymphocyte types) and granulocyte-macrophage progenitor cells (i.e. precursors to granulocytes and monocytes). in mice and presumably humans, gata2 deficiency also leads to reduced levels of early erythrocyte stem cells. while our understanding of human hematopoiesis is incomplete, it is proposed that these or related progenitor cell reductions causes a progressively worsening depletion of circulating and/or tissue bound b cells, nk cells, t helper cells, monocytes, plasmacytoid dendritic cells, neutrophils, and/or red 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. however, the role of gata2 deficiency in leading to a leukemias is not understood, particularly since mutations which increase the activity of this transcription factor appear to be associated with the progression of non-familial aml as well as development of the blast crisis in chronic myelogenous leukemia. immunologic defects the depletion of hematologic cells, particularly dendritic cells, caused by gata2 deficiency (see previous section) also appears responsible for the development of defective innate and adaptive immune responses. in consequence, these individuals become increasing susceptibility to infectious agents and to cancers caused by infective agents. this defect in mounting immune responses is mostly restricted to new antigenic challenges. that is, secondary immune responses to which individuals had mounted effective primary immune responses before gata2 deficiency paralyzed their immune system generally remain intact. immune system deterioration would also appear responsible for the development of the pathological autoimmune reactions which affected individuals may mount against their own tissues. lymphedema 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. hearing loss 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. other defects the pathophysiology behind the other defects associated with gata2 deficiency such as hypothyroidism, endocarditis, pulmonary alveolar proteinosis; cryptogenic organizing pneumonia-like disease, pulmonary hypertension, pulmonary ventilator and diffusion defects, miscarriages, etc., is as yet undefined. it is possible that many of these other defects are secondary, i.e. associated with gata2 deficiency but not a direct result of low cellular levels of the gata2 transcription factor. diagnosis individuals with gata2 deficiency commonly exhibit abnormalities in their circulating blood cells (see above "hematologic" section of signs and symptoms) that may precede other signs and symptoms of the disease by years. their bone marrow typically shows significant reductions in one or more types of blood cell lines (i.e. hypocellularity) with characteristic dysplastic features of increased sizes of cells in the red blood cell line (i.e. macrocytic erythropoiesis), small or enlarged megakaryocytes, abnormalities in the maturation of cells in the granulocyte cell line, fibrosis consisting of reticular fibers, increased numbers of t cells containing numerous large granules in their cytoplasm, and in advanced cases increases in blast cell numbers. the bone marrow in advanced cases may also exhibit increase in cellularity, i.e. hypercellularity. gata2 deficient individuals often have highly increased blood levels of fms-like tyrosine kinase 3 ligand however, these as well as other features are diagnostic of a hematologic disorder but not necessarily of gata2 deficiency. dna sequencing of the full gata2 gene coding region including the intron4 enhancer by sanger sequencing or high-throughput methods along with dna copy number analysis and karyotyping should establish the presence of gata2 gene mutations; comparison of detected gene mutations to the list of inactivating gata2 gene mutations plus the clinical presentation and family history are essentials in making the diagnosis of gata2 deficiency. treatment 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. however, due to the uncommonness of, and only recent appreciation for, the disease, standard phase 2 clinical trials to establish the efficacy of a drug(s), and/or non-drug treatment regiments against an appropriate placebo treatment regimen have not been reported. family counseling family members of an individual(s) diagnosed with an inactivating gata2 gene mutation should be told of their chances of having this mutation, advised of the consequences of this mutation, recommended to be tested for the mutation, warned that they are not suitable donors for any gata2 deficient individual, and offered long term follow up of their mutation. prevention of complications recommendations for individuals exhibiting susceptibility to the infectious complications of gata2 deficiency (e.g. monomac-affected individuals) include: early vaccination for papillomavirus, early vaccination or prophylaxis drug treatment for nontuberculosus mycobacteria, and, perhaps, prophylaxis drug treatment (e.g. azithromycin) for bacteria. 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. gata2 deficient individuals should be routinely monitored by: a) frequent complete blood counts and when indicated bone marrow examinations to detect progression of their disorder to more mds or leukemia; b) and clinical evaluation of respiratory function and when indicated lung function tests to detect deterioration of lung function; and c) clinical evaluation analyses to determine the infection susceptibility, tumor formation, and the worsening function of other organs. bone marrow transplantation many authorities currently recommend gata2 deficiency be treated by a moderately but not maximally aggressive myeloablative conditioning regimen to remove native bone marrow stem/progenitor cells followed by hematopoietic stem cell transplantation to repopulate the bone marrow with gata2 sufficient stem cells. the use of this procedure should be anticipatory and occur before the development of a hyperellular bone marrow or a bone marrow or blood populated by an excess of progenitor cells (i.e. blast cells >2% to 5%). these developments are often followed by transformation of the disorder to a leukemia. this regiment should also be performed before the development of severe systemic infections, tumors, or deterioration in lung function. 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. the regimen also improves or normalizes lung function in cases of pulmonary alveolar proteinosis and pulmonary artery hypertension and may halt the progression or improve the function of other organs directly injured by gata2 deficiency. clinical trials 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. the trial had 8 disease-free survivors and obtained an overall survival 76 months with