Disruption of the N-terminal domain in a STAT3 hyper-IgE syndrome variant causes disease by sequestering STAT3 in the cytoplasm.
Joseph Mackie, Dan Suan, David B Langley et al.
✦ AI-curated · Sources linked
Case in brief
A patient with a STAT3 R31Q variant presented with disseminated invasive aspergillosis involving the brain and lung, bronchiectasis, and elevated serum IgE, without nonimmune manifestations of hyper-IgE syndrome. Cell-line studies showed reduced STAT3 abundance and transcriptional activity, with R31Q exerting a negative-dominant effect: mutant–wild-type dimers were preferentially formed and retained in the cytoplasm, limiting nuclear translocation. Patient lymphocytes showed reduced memory B cells, MAIT cells, and TH17 cytokines, while several other measured immune features were preserved or only partly impaired.
What made this case unusual
The disease-associated variant affected STAT3’s N-terminal domain, rather than the domains commonly implicated in STAT3 hyper-IgE syndrome, and caused disease through cytoplasmic sequestration of mutant–wild-type dimers.
Diagnostic / clinical pearl
STAT3-related hyper-IgE syndrome can involve an N-terminal variant and present with invasive aspergillosis and bronchiectasis despite absence of nonimmune manifestations; domain location alone should not exclude the diagnosis.
Why it matters
The findings identify a mechanism in which altered dimerization and cytoplasmic retention impair STAT3 function, extending understanding of how STAT3 variants can produce this syndrome.