Dominant-Negative Versus Gain-of-Function STAT3 Defects: A Systematic Review on Epidemiological, Clinical,...

Area of Science:

• Immunology
• Genetics
• Clinical Medicine

Background:

• Germline mutations in signal transducer and activator of transcription 3 (STAT3) are associated with two distinct clinical syndromes.
• These syndromes present with either a predominant infectious or autoimmune phenotype.

Purpose of the Study:

• To systematically review and compile existing literature on gain-of-function (GOF) and dominant-negative (DN) mutations in the STAT3 gene.
• To analyze and compare the clinical manifestations and immunological profiles associated with STAT3-DN and STAT3-GOF mutations.

Main Methods:

• A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases.
• The search covered publications from 1990 to 2023, including manual searching of major reviews and full-text articles.
• Data from 107 articles reporting on 490 patients were analyzed.

Main Results:

• Significant clinical differences were observed between STAT3-DN (265 patients) and STAT3-GOF (225 patients) cohorts.
• STAT3-DN patients exhibited higher rates of infectious complications (98.2%), pneumonia (67.3%), sinusitis (17.5%), otitis (27.7%), abscesses (52.7%), and dermatologic manifestations (88.3%), along with elevated IgE levels.
• STAT3-GOF patients showed a higher incidence of interstitial lung disease (17.7%), endocrinopathies (16.5%), and early-onset polyautoimmunity, often requiring immunosuppressive therapy. Lymphocyte subset analysis revealed distinct patterns, with STAT3-DN patients having higher CD3+ T cells and lower NK cells, while STAT3-GOF patients had lower CD4+ T cells.

Conclusions:

• STAT3-DN mutations are characterized by recurrent infections, eczema, elevated IgE, and eosinophilia.
• STAT3-GOF mutations are associated with early-onset polyautoimmunity and a frequent need for immunosuppressive treatments.
• These findings highlight the contrasting clinical phenotypes driven by different types of germline STAT3 mutations.