Signal Transducer and Activator of Transcription 3 (STAT3) Variant p.K709N Causes Hyper‐IgE Syndrome Likely by Impaired STAT3‐Dimer Formation

TL;DR

A new STAT3 mutation, p.K709N, causes hyper-IgE syndrome by disrupting STAT3 dimer formation and gene expression.

Contribution

Identifies a novel STAT3 variant p.K709N as a cause of hyper-IgE syndrome through impaired dimerization.

Findings

The STAT3 p.K709N variant impairs dimer formation and DNA binding.

The mutation leads to reduced target gene expression and a dominant-negative effect.

3D structural analysis shows K709 is critical for dimer stabilization.

Abstract

STAT3‐hyper‐IgE syndrome (STAT3‐HIES) is an inborn error of immunity caused by heterozygous dominant‐negative mutations in the signal transducer and activator of transcription 3 (STAT3). In this study, we evaluate the functional relevance of a previously undescribed heterozygous STAT3 variant in a patient with clinical findings of STAT3‐HIES. Flow cytometry, quantitative real‐time PCR, pull‐down assays, native PAGE, DNA‐binding ELISA, and 3D‐structural data analysis were performed. Genetic analysis identified the heterozygous STAT3 variant NM_139276.2:c.2127G>C (NP_644805.1:p.(K709N); short: p.K709N) in a patient with a clinical and laboratory phenotype characteristic of STAT3‐HIES, including early onset severe eczema, chronic lung disease, eosinophilia, and elevated serum IgE levels. While STAT3 p.K709N did not significantly affect STAT3 phosphorylation, STAT3 target gene expression was impaired in patient cells. Expression of STAT3 p.K709N and wild‐type STAT3 in STAT3‐deficient cells indicated a dominant‐negative effect by the mutation. Analysis of 3D‐structural data and modeling suggested a central role of the affected amino acid K709 in stabilizing a C‐terminal loop in STAT3 essential for dimer formation. Consequently, p.K709N resulted in diminished STAT3 dimerization and reduced DNA binding in patient cells. Functional analyses verified STAT3 p.K709N to cause STAT3‐HIES and suggest that STAT3 p.K709N impairs STAT3 dimer formation.

In a patient with the classical clinical phenotype of STAT3‐hyper‐IgE syndrome, we identified the previously unreported STAT3 variant p.K709N to be disease‐causing. Molecular analyses revealed that STAT3 p.K709N exerts a dominant‐negative effect, leading to impaired STAT3 dimerization and reduced STAT3 target gene expression. Source: Created in BioRender. Hagl B. (2025) https://BioRender.com/80tycxp.

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