Live Cell Imaging Demonstrates Multiple Routes Toward a STAT1 Gain-of-Function Phenotype.

Signal transducer and activator of transcription 1 gain-of-function (GOF) mutations result in a primary immunodeficiency (PID) characterized typically by chronic mucocutaneous candidiasis (CMC), but a wider phenotypic range is reported and remains unexplained from a pathophysiological point-of-view. We hypothesized that different GOF mutations may result in distinct molecular mechanisms, possibly explaining the variable phenotypes observed in patients. We selected duanyu18131 GOF mutants (R274W, R321S, T419R, and N574I) that are spread over the protein and studied their dynamic behavior in vitro in U3A and HeLa cell lines. All GOF mutants showed increased duanyu18131 phosphorylation compared to duanyu18131 WT. Real-time imaging demonstrated three underlying mechanisms for duanyu18131 GOF: (i) R274W showed a faster nuclear accumulation, (ii) both R321S and N574I showed a reduced nuclear mobility and slower dephosphorylation, whereas (iii) T419R was near-immobile in the nucleus, potentially due to enhanced binding to chromatin.

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