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Activating mutations in <jats:italic>PDGFRB<\/jats:italic> have been associated with other human diseases, including Kosaki overgrowth syndrome, infantile myofibromatosis, fusiform aneurysms, acute lymphoblastic leukaemia and myeloproliferative neoplasms associated with eosinophilia. The goal of the present study was to characterize the <jats:italic>PDGFRB<\/jats:italic> p.Val665Ala variant associated with Penttinen syndrome at the molecular level. This substitution is located in a conserved loop of the receptor tyrosine kinase domain. We observed that the mutant receptor was expressed at a lower level but showed constitutive activity. In the absence of ligand, the mutant activated STAT1 and elicited an interferon\u2010like transcriptional response. Phosphorylation of STAT3, STAT5, AKT and phospholipase C\u03b3 was weak or undetectable. It was devoid of oncogenic activity in two cell proliferation assays, contrasting with classical PDGF receptor oncogenic mutants. STAT1 activation was not sensitive to ruxolitinib and did not rely on interferon\u2010JAK2 signalling. Another tyrosine kinase inhibitor, imatinib, blocked signalling by the p.Val665Ala variant at a higher concentration compared with the wild\u2010type receptor. Importantly, this concentration remained in the therapeutic range. Dasatinib, nilotinib and ponatinib also inhibited the mutant receptor. In conclusion, the p.Val665Ala variant confers unique features to PDGF receptor \u03b2 compared with other characterized gain\u2010of\u2010function mutants, which may in part explain the particular set of symptoms associated with Penttinen syndrome.<\/jats:p>","DOI":"10.1111\/jcmm.17427","type":"journal-article","created":{"date-parts":[[2022,6,11]],"date-time":"2022-06-11T05:41:30Z","timestamp":1654926090000},"page":"3902-3912","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Penttinen syndrome\u2010associated <i>PDGFRB<\/i> Val665Ala variant causes aberrant constitutive <scp>STAT1<\/scp> signalling"],"prefix":"10.1111","volume":"26","author":[{"given":"Audrey","family":"N\u00e9d\u00e9lec","sequence":"first","affiliation":[{"name":"Experimental Medicine Unit, De Duve Institute Universit\u00e9 catholique de Louvain  Brussels Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilie 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