Alt. symbols: STAT5

Approved name: signal transducer and activator of transcription 5B
Alt. names: signal transducer and activator of transcription 5B | transcription factor STAT5B

Location: 17q21.2: 42199176 - 42288633 (-)
Gene type: protein_coding, 30 transcripts.

Scores: LoFtool: 0.091700 | pLI: 0.99995316 | LOEUF: 0.220

HGNC: 11367

NCBI: 6777, RefSeq: NG_007271.1

Ensembl: ENSG00000173757.11

LRG_192 | Status: public

OMIM: 604260

Expression | ProteinAtlas

STAT5B encodes a transcription factor belonging to the signal transducer and activators of transcription (STAT) family and harboring a high degree of sequence homology (~94%) with STAT5A. In response to ligand binding, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. They are activated by and mediate the responses of many cytokine, mitogens and signaling factors such as such as IL2, IL3, IL7 GM-CSF, erythropoietin, thrombopoietin, and different growth hormones.

Recurrent gain-of-function somatic mutations in both STAT5A and STAT5B have been reported in hematopoietic malignancies, though more frequently and prominently for the latter (PMID: 20508164, 30679796, 31123029). Somatic activating heterozygous missense STAT5B mutations in the SH2 or TAD domains have been recurrently associated with lymphomas (PMID: 26415585, 25586472, 26192917) and STAT5B-RARA fusion is associated with a form of acute promyelocytic leukemia [MIM:102578]. Monoallelic and biallel ic germline mutations in STAT5B have been associated with autosomal dominant (AD) and recessive (AR) forms of growth hormone (GH) insensitivity with immunodeficiency, respectively [OMIM: 618985, 245590]. Both are characterized by short stature due to GH insensitivity, failure to thrive, delayed bone age, and delayed puberty associated with decreased serum levels of IGF1. AR patients may have dysmorphic features and most but not all patients reported thus far have shown evidence of immunodeficiency and/or immune dysregulation, including recurrent and/or severe infections from susceptibility to viruses and opportunistic pathogens, chronic lung disease, lymphoid interstitial pneumonitis, eczema, and autoimmune arthritis. In contrast, the 3 families of AD patients did not have histories of recurrent infections and only 1 patient was reported to have chronic lung disease, but asthma, celiac disease, autoimmune thyroiditis and eczema were present. Labs in the AR patients showed associated quantitative and/or functional T cell deficits, including in the number and function of FOXP3+ Tregs; NK cell populations could also be affected. In contrast, the AD patients had mild elevations of IgE but largely normal immunoglobulin levels and lymphocyte subsets (though patient II-2 from Family 1 did show low to low normal levels of T, B and NK cells, particularly CD8+ T cells). Like the other STAT proteins, STAT5B contains a 4-alpha helix coiled-coiled domain (CCD), a DNA-binding domain (DBD), an SH2 (src-homology 2) domain for docking to phosphorylated tyrosines, and a C-terminal transcriptional activation domain (TAD). All the AR missense, nonsense and frameshift mutations characterized to date lack functional SH2 and downstream TAD domains, and result in little or no detectable protein. In contrast, the 3 heterozygous missense mutations identified by Klammt et al. (2018) in the AD patients retained the capability to become tyrosine phosphorylated upon GH stimulation and to dimerize with wild-type STAT5B protein, but exerted dominant negative effects upon the latter. One CCD domain (p.Gln177Pro) mutation abrogated nuclear import, while two DBD mutations (p.Gln474Arg, p.Ala478Val) impaired the ability of the transcription factor dimer to bind canonical STAT5B DNA response elements. [Load More]