STAT3Mutations in the Hyper-IgE Syndrome

Abstract

Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.

A novel mutation in the linker domain of the signal transducer and activator of transcription 3 gene, p.Lys531Glu, in hyper-IgE syndrome

“…MCs might mediate these effects by releasing autacoids; granule-associated molecules, such as tryptase; and the cytokines IL-13 and TNF. 2 Indeed, expression of IL-13 by the MCs localized within the BSM bundles is observed in patients with mild and severe asthma. 3 We here provide evidence that the recently described epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) might also be implicated in this process.…”

“…1 Recently, mutations in the signal transducer and activator of transcription factor 3 gene (STAT3) have been determined to be the cause of autosomal dominant HIES. 2,3 Most STAT3 mutations were located in the DNA-binding domain or Src homology 2 domain, whereas missense mutations were also found in the transactivation domain downstream of the Src homology 2 domain. [2][3][4] Here we report the first STAT3 mutation in the linker domain of the protein in a boy with HIES.…”

“…2,3 Most STAT3 mutations were located in the DNA-binding domain or Src homology 2 domain, whereas missense mutations were also found in the transactivation domain downstream of the Src homology 2 domain. [2][3][4] Here we report the first STAT3 mutation in the linker domain of the protein in a boy with HIES.A 5-year-old Korean boy was admitted because of fever, cough, and otorrhea for a week. His parents were not consanguineous.…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…While a drug may inhibit a pathway critical for cancer cell proliferation or survival, it is equally important that it is not toxic to normal cells. Evidence from experimental systems to human genetic analyses has provided strong support for reasoning that the activity of specific STAT family members can be lost from normal cells without severe consequence, likely due to redundancies in transcriptional regulation under physiologic conditions [127,128]. Taken together, these findings suggest that STATs are valuable targets for cancer therapy.…”

Antibody deficiency diseases

“…those known to be involved in a given PID, may give rise to a different phenotype, suggesting that the field is getting more complex than previously recognized. In addition, the etiology of several phenotypically similar, albeit in some cases not entirely identical, PID have recently been shown to be caused by mutations in other genes than those originally implicated (examples include hyper-IgM (HIGM, see below), X-linked lymphoproliferative syndrome [8], hyper-IgE [9,10], Omenn syndrome [11] and X-linked susceptibility to mycobacterial infections [12]. Differences in glycosylation pattern may also account for selected disease phenotypes [13] and understanding the full spectrum of genetic causes of PID still requires substantial efforts.…”