STAT3-gene

The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, members of the STAT family are phosphorylated by the receptor-associated kinases and then form homo- or heterodimers that translocate to the nucleus where they act as transcriptional activators.

The STAT3 gene plays a role in regulating the host response to viral and bacterial infections. Mutations in this gene lead to complex clinical deficits such as susceptibility to infection, immune dysregulation as well as characteristic non-immunological features (Olbrich P et al. 2018). Thus, STAT3 mutations are associated with multisystem autoimmune disease in childhood and hyper-immunoglobulin E syndrome 1.

STAT3-GOF mut ations: A review paper (Fabre A et al. 2019) summarized all available cases with STAT3-GOF mutations:

28 different mutations have been described. Early disease onset with an average age of 3 (0.5-5) years is characteristic of this mutational form. The most common manifestations were.

• autoimmune cytopenias (28 of 42)
• Lymphoproliferation (27 of 42)
• enteropathy (24 of 42)
• interstitial lung disease (15 of 42)
• thyroiditis (13 of 42)
• diabetes (10 of 42) and
• Postnatal growth failure (15 of 21).
• Immunodeficiency was not always a predominant feature.

Most patients required significant immunosuppressive therapy. 5 patients received hematopoietic stem cell transplantation, and 4 died from complications.

An activating STAT3 mutation caused neonatal diabetes mellitus (Saarimäki-Vire J et al 2017).

1. Fabre A et al (2019) Clinical Aspects of STAT3 gain-of-function germline mutations: A Systematic Review. J Allergy Clin Immunol Pract. 7:1958-1969
2. Olbrich P et al (2018) STAT1 and STAT3 mutations: important lessons for clinical immunologists. Expert Rev Clin Immunol 14:1029-1041.
3. Saarimäki-Vire J et al (2017) An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation. Cell Rep 19:281-294.