Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome

Abstract

Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.

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

“…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. TSLP is known to initiate typical IgE-and T H 2 cell-dependent allergic diseases through its effects on dendritic cells, whereas its ability to potently stimulate MCs might contribute to the T cell-and IgE-independent allergic inflammation.…”

“…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.…”

“…It was reported that STAT3 mutations were not always found in patients with HIES. 3,4 In addition, homozygous mutations in the tyrosine kinase 2 gene are the genetic defect in a subgroup of patients with HIES. 6 The K531E mutation described in this report is the first mutation in the linker domain of STAT3, further expanding the genetic heterogeneity of HIES.…”

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.…”