gata2 deficiency gata2 deficiency 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. being the gene haploinsufficient, mutations that cause a reduction in the cellular levels of the gene's product, gata2, are autosomal dominant. 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. gata2 deficiency is a life-threatening and precancerous condition. gata2 deficiencyother namesgata2 haploinsufficiency, gata2 deficiency syndrome 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. each of these presentations is characterized by a specific constellation of signs and symptoms but often includes signs and symptoms more characteristic of other gata2 deficiency presentations. furthermore, individuals with identical gata2 gene mutations can exhibit very different presentations. prior to 2011, monomac and the emberger syndrome were clinically defined as unrelated genetic disorders. in 2011, however, all cases of both disorders were found to be caused by inactivating mutations in the gata2 gene. subsequently, some but not all cases of an expanding list of other well-defined disorders have been attributed to inactivating gata2 mutations. while monomac, the emberger syndrome, and the growing list of all other disorders marked by inactivating gata2 gene mutations are now being classified as a single clinical entity termed gata2 deficiency, monomac and the emberger syndrome are sometimes still regarded as separate clinical entities. here, gata2 deficiency is taken to include all disorders caused by inactivating gata2 mutations. defined as such, gata2 deficiency is an unexpectedly common underlying cause for a growing list of disorders. importantly, however, its treatment differs critically from that used to treat cases of these disorders which are not due to gata2 deficiency. presentations 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. in most cases, the age of onset and initial signs and symptoms are variable with each presentation often being accompanied by signs or symptoms more typical of other presentations. nonetheless, most cases of the deficiency exhibit a combination of signs and symptoms that fit the following presentations. monomac main article: monomac individuals affected by monomac commonly present in early adulthood affected by one or more of the opportunistic infections listed in the above signs and symptoms section and have profoundly low numbers of circulating monocytes which may have existed for many years before symptoms developed. these individuals also have low numbers of two other types of circulating blood cells viz., b lymphocytes and nk cells. other presentations and/or developments (see signs and symptoms) include: 1) pulmonary alveolar proteinosis; 2) tumors caused by opportunistic viral infections; 3) autoimmunity disturbances; and 4) the myelodysplastic syndrome, acute myeloblastic leukemia, or chronic myelomonocytic leukemia. emberger syndrome main article: emberger syndrome emberger syndrome presents as early as infancy but more typically in childhood or early adulthood with lymphedema of the lower limbs or testes, i.e. hydrocele, and congenital sensorineural hearing loss. affected individuals may also exhibit one or more of the dysplasias listed in the above "signs and symptoms" section. 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. individuals affected by the syndrome may also exhibit increased susceptibility to opportunistic viral infections, particularly in individuals that have null mutations (i.e. mutations that cause complete lose of a functional gene product) in the gata2 gene. familial mds/aml main article: myelodysplastic syndrome familial mds/aml is an inherited predisposition to develop mds, i.e. a disorder characterized by the development of a genetically distinct subpopulation (i.e. clone) of bone marrow hematopoietic stem cells, decreased levels of one or more types of circulating blood cells, and an increased risk of progressing to leukemia, particularly aml. gata2 deficiency commonly presents as mds in childhood (usually >4 years of age) and adolescent (generally <18 years of age) individuals and as such is the most common germline mutation responsible for familial mds/aml in this age group. inactivating gata2 mutations appear responsible for ~15% in cases of advanced familial mds (i.e. cases in which hematologic blast cells are ≥2% in blood or ≥2% but ≤20% in bone marrow) and in 4% of cases diagnosed as low-grade familial mds (i.e. blast cells are <2% in blood or <5% in blood). individuals exhibiting >20% blast cells in blood or bone marrow are diagnosed as having aml. thus, gata2 deficiency may also present as aml that was preceded by mps. in about 70% of the cases, the inactivating gata2 mutations found in familial mds/aml are associated with advanced disease and exhibit monosomy of their 7 chromosome. gata2 deficiency-induced familial mds/aml is often diagnosed in one member of a family that has other members with identical gata2 gene mutations but either are classified as having another type of gata2 deficiency presentation or have no signs or symptoms whatsoever of gata2 deficiency. congenital neutropenia main article: neutropenia congenital neutropenia refers to an assorted group of diseases that share a common set of signs and symptoms, viz., neutropenia, i.e. a low circulating blood neutrophil count, increased susceptibility to infections, various organ dysfunctions, and an extraordinarily high risk of developing leukemia. 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. this presentation often persists for years but commonly progresses to include thrombocytopenia, increases susceptibility to infections due to, e.g. atypical mycobacteria or human papillomavirus, dysfunction of non-hematological organs, mds, and leukemia (primarily aml and less commonly cmml). it is estimated that by age 30, 60% of these individuals develop leukemia. some of these individuals have large deletion mutations that span the gata2 along with nearby genes and exhibit in addition to hematological defects various developmental abnormalities, neurological abnormalities, and/or body dysmorphic disorders. other presentations main article: aplastic anemia main article: bone marrow failure main article: humoral immune deficiency main article: monocytosis main article: chronic myelomonocytic leukemia gata2 deficiency has been diagnosed in up to 10% of individuals presenting with aplastic anemia. it is also the most common cause of hereditary bone marrow failure and may present with this disorder. gata 2 deficiency has been diagnosed in rare cases presenting as humoral immune deficiency due to b cell depletion, severe epstein–barr virus infection, or epstein-barr associated cancers. in all of these presentations, individuals may have or develop other manifestations of the deficiency and are of particularly high risk for developing aml or cmml. rare cases of individuals with gata2 deficiency may also present with extreme monocytosis (i.e. increases in circulating blood monocytes) or cmml, i.e. monocytosis plus the presence of abnormal (blasts) in the circulation and/or bone marrow. gata2 deficient individuals who develop cmml often exhibit mutations in one of their asxl1 genes. since mutations in this gene are associated with cmml independently of gata2 mutations, asxl1 mutations may promote the development of cmml in gata2 deficiency. symptoms the age of onset of the gata2 deficiency is variable with rare individuals showing first signs or symptoms in their infancy and others showing first symptoms or signs at almost any time thereafter including their later years. rare individuals with inactivating gata2 mutations may never develop symptoms, i.e. the disorder has a very high but nonetheless incomplete degree of penetrance. this variability can occur between members of the same family who are documented to have the same gata2 mutation. the many signs and symptoms that are the direct or indirect consequences of gata2 deficiency organized based on the types of involvement are: hematologic: aplastic anemia, chronic neutropenia, monocytopenia, monocytosis (rarely), thrombocytopenia (which unlike other hematologic findings is most often due to autoimmunity), bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, case reports of chronic lymphocytic leukemia and large granular lymphocytic leukemia. lymphatic: lymphedema, i.e. fluid retention and tissue swelling caused by a compromised lymphatic system of the lower extremities (often complicated by deep vein thrombosis and cellulitis), lymphedema in other sites such as the face or testes (i.e. hydrocele). immunologic: increased susceptibility to infections caused by human papillomavirus, herpes simplex, varicella zoster virus, epstein–barr virus, cytomegalovirus, molluscum contagiosum virus, nontuberculous mycobacteria, other bacteria, various aspergillus fungus species, various candida fungus species, and histoplasma capsulatum; tumors: increased incidence of human papillomavirus-induced (e.g. bowenoid papulosis, warts, etc.)) and epstein-barr virus-associated (e.g. nasopharynx cancer, t cell non-hodgkin lymphoma ) benign and malignant tumors. cancers: increased incidence of metastatic melanoma, cervical carcinoma, bowen disease of the vulva, spindle cell sarcoma of the liver, head and neck cancers, leiomyosarcoma, pancreas cancer, kidney cancer, and breast cancer. autoimmunity: erythema nodosum, panniculitis, lupus erythematosus-like reactions, autoimmune thrombocytopenia, chronic arthritis, arthralgias, primary biliary cirrhosis, aggressive multiple sclerosis. lung: pulmonary alveolar proteinosis (unlike most other cases of pulmonary alveolar proteinosis, the gata2 deficiency-induced lung disorder is not caused by autoimmunity to or other causes for sharp reductions in granulocyte-macrophage colony stimulating factor); cryptogenic organizing pneumonia-like disease, pulmonary artery hypertension; pulmonary ventilation and diffusion defects as defined by pulmonary function testing that may lead to respiratory failure. neuorlogic: sensorineural hearing loss mainly for high frequencies. heart: endocarditis (may reflect gata2 deficiency in the endocardium and/or impaired overlap with gata4 function, which is involved in the embryonic development of this organ). thyroid gland: idiopathic (i.e. unknown cause) hypothyroidism. reproductive: high rate of miscarriage. body dysmorphic disorders: hypotelorism, epicanthic folds, webbed neck, small palpebral fissures, ptosis, strabismus, urogenital malformations. emotional and behavioral disorders: autism spectrum disorders, chronic headache. genetics gata2 transcription factor the gata2 transcription factor contains two zinc finger (i.e. znf) motifs. c-znf is located toward the protein's c-terminus and is responsible for binding to specific dna sites. n-znf is located toward the proteins n-terminus and is responsible for interacting with various other nuclear proteins that regulate its activity. the transcription factor also contains two transactivation domains and one negative regulatory domain which interact with nuclear proteins to up-regulate and down-regulate, respectively, its activity. in promoting haematopoiesis (i.e. maturation of hematological and immunological cells), gata2 interacts with other transcription factors (viz., runx1, scl/tal1, gfi1, gfi1b, myb, ikzf1, transcription factor pu.1, lyl1) and cellular receptors (viz., mpl, gpr56). gata2 binds to a specific nucleic acid sequence viz., (t/a(gata)a/g), on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. however, there are thousands of sites in human dna with this nucleotide sequence but, for unknown reasons, gata2 binds to <1% of these. furthermore, all members of the gata transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with gata2 binding or even displace the gata2 that is already bound to these sites. 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. this displacement phenomenon is termed the "gata switch". in all events, the actions of gata2 in regulating its target genes is extremely complex and not fully understood. gata2 gene mutations inactivating mutations in the gata2 gene are the primary cause of gata2 deficiency disorders. this gene is a member of the evolutionarily conserved gata transcription factor gene family. all vertebrate species tested so far, including humans and mice, express 6 gata genes, gata1 through gata6. the human gata2 gene is located on the long (or "q") arm of chromosome 3 at position 21.3 (i.e. the 3q21.3 locus). it consists of 8 exons. two sites, one more toward the 5' end, the second more toward the 3' end of