The *STING1* gene encodes the STING protein (stimulator of interferon genes), a key player in the body's defense against viral infections and pathogens through the production of type I interferon triggered by the detection of cytoplasmic DNA. Certain mutations in this gene lead to its constitutive activation and are responsible for an autoinflammatory disorder termed SAVI (STING-associated vasculopathy with onset in infancy), characterized by blood vessel occlusions, necrosis of the extremities, myositis, skin rashes, and pulmonary inflammation; a lupus-like presentation may also be observed. Understanding the genetics of the human *STING1* gene is of both fundamental and translational interest, all the more so as STING constitutes a therapeutic target under investigation in cancers and infectious diseases.
In this context, the authors generated an induced pluripotent stem cell (iPSC) line from the cells of a seven-year-old female patient carrying a rare heterozygous *STING1* variant (c.463G > A, leading to the p.V155M substitution), a dominant gain-of-function mutation inherited from her father, who was also affected. The patient presented with a complex systemic inflammatory syndrome combining vasculopathy, pulmonary fibrosis, and autoimmunity. Cryopreserved peripheral blood mononuclear cells were reprogrammed using non-integrating Sendai viral vectors expressing the OCT4, SOX2, c-MYC, and KLF4 factors. Colonies displaying a typical pluripotent stem cell morphology were manually selected in order to establish a feeder-free cultured line.
The resulting line underwent comprehensive genotypic and functional characterization. SNP array analysis, comparing the iPSC line with the parental cells, confirmed a normal karyotype, the absence of aneuploidies, deletions, or insertions, as well as genotype concordance attesting to the origin of the cells. Resequencing of the mutated site confirmed the presence of the heterozygous c.463G > A mutation. The line expressed the pluripotency markers OCT4 and SOX2 by immunocytochemistry, as well as TRA-1-81 (85%) and SSEA-4 (97%) by flow cytometry. Its capacity to differentiate spontaneously into the three germ layers was verified by embryoid body formation, followed by molecular analyses: the cells showed expression levels comparable to the reference without lineage bias and expressed ectodermal (β-III-tubulin), mesodermal (α-smooth muscle actin), and endodermal (α-fetoprotein) proteins. Mycoplasma contamination tests were negative.
This iPSC line carrying the *STING1* mutation constitutes a tool intended to explore the cellular mechanisms leading to the disease.