STAT3-confusion-of-function: Beyond the loss and gain dualism

Background: Germline mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for 2 distinct human diseases: autosomal-dominant hyper-IgE syndrome (AD-HIES) caused by STAT3 loss-of-function mutations and STAT3 gain-of-function disease. So far, these entities have been regarded as antithetic, with AD-HIES mainly associated with characteristic infections and a connective tissue phenotype and STAT3 gain-of-function characterized by lymphoproliferation and poly-autoimmunity. The R335W substitution in the DNA-binding domain of STAT3 was initially described in 2 patients with typical AD-HIES, but paradoxically, recent functional analysis demonstrated a gain-of-function effect of this variant. Objectives: A patient with Sjogren syndrome and features of AD-HIES with this mutation is described and the molecular consequences are further characterized. Methods: This study provides a clinical and immunological description of the patient. STAT phosphorylation in primary patient cells was studied and A4 cells transfected with the patient allele were used to study phosphorylation kinetics, transcriptional activity, and target-gene induction. Results: The hybrid clinical features of the patient were associated with normal T(H)17 cells. Enhanced and prolonged STAT3 phosphorylation, an increased STAT3 driven luciferase reporter activity upon IL-6 stimulation, but reduced IL-6-induced SOCS3 production were all observed. Conclusions: The germline R335W-STAT3 variant displays a mixed behavior in vitro that mainly shows gain-of-function, but also loss-of-function features. This is matched by an ambiguous clinical and immunological phenotype that dismantles the classical antithetic dualism of gain-versus loss-of-function. Germline STAT3 mutation-related disease represents a pathological spectrum with the p.R335W associated phenotype locating between the 2 recognized clinical disease patterns.

Automated summary

This study describes a patient with Sjogren syndrome and features of AD-HIES caused by a germline R335W-STAT3 variant. The study provides insights into the clinical and immunological phenotype, as well as the molecular consequences of this variant. The findings suggest that the R335W-STAT3 variant displays both gain-of-function and loss-of-function features, challenging the traditional dualism of gain-versus loss-of-function.