<unk>  transcription factor The<unk>  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),<unk>  interacts with other transcription factors (viz., RUNX1, SCL/TAL1, GFI1, GFI1b, MYB, IKZF1, Transcription factor PU.1, LYL1) and cellular receptors (viz., MPL, GPR56).<unk>  binds to a specific nucleic acid sequence viz., (T/A<unk> 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,<unk>  binds to <1% of these. Furthermore, all members of the<unk> transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with<unk>  binding or even displace the<unk>  that is already bound to these sites. For example, displacement of<unk>  bond to this sequence by the<unk>  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<unk>  in regulating its target genes is extremely complex and not fully understood.<unk>  gene mutations Inactivating mutations in the<unk>  gene are the primary cause of<unk>  disorders. This gene is a member of the evolutionarily conserved<unk> transcription factor gene family. All vertebrate species tested so far, including humans and mice, express 6<unk> genes,<unk>  through<unk> . The human<unk>  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 the gene code for two Zinc finger structural motifs, ZF1 and ZF2, respectively, of the<unk>  transcription factor. ZF1 and ZF2 are critical for regulating the ability of<unk>  transcription factor to stimulate its target genes. The<unk>  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<unk>  expression is highly complex. For example, in hematological stem cells,<unk>  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,<unk>  stimulates production of Interleukin 1 beta and CXCL2 which act indirectly to simulate<unk>  expression. In an example of a negative feedback circuit, the<unk>  transcription factor indirectly causes activation of the G protein-coupled receptor, GPR65, which then acts, also indirectly, to repress<unk>  gene expression. In a second example of negative feed-back,<unk>  transcription factor stimulates the expression of the<unk>  transcription factor which in turn can displace<unk>  transcription factor from its gene-stimulating binding sites thereby limiting<unk> 's actions (see<unk>  switch in<unk>  transcription factor" section). The human<unk>  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<unk> mutations have been associated with<unk> ; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the<unk>  transcription factor's ZF1, ZF2, and 9.5 kb sites. Rare cases of<unk>  involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of<unk> mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances. Non-mutational<unk>  Analyses of individuals with AML have discovered many cases of<unk>  in which one parental<unk>  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<unk>  in other disorders as well to integrate it into the diagnostic category of<unk> . Other genetic abnormalities<unk>  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<unk> , 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.<unk>  is also associated with somatic mutations in at least three other genes viz., ASXL1, SETBP1, and STAG2. Independently of<unk>  mutations and the development of<unk> , 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<unk>  are unclear and require further study.
GATA2 deficiency
WNT4 deficiency
Janus kinase 3 deficiency
ZC4H2 deficiency
CDK13-related disorder
LRBA deficiency
ZAP70 deficiency
1p36 deletion syndrome