Penttinen syndrome-associated PDGFRB Val665Ala variant causes aberrant constitutive STAT1 signalling

J Cell Mol Med. 2022 Jul;26(14):3902-3912. doi: 10.1111/jcmm.17427. Epub 2022 Jun 10.


Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and characterized by a prematurely aged appearance with lipoatrophy, skin lesions, thin hair and acro-osteolysis. Activating mutations in PDGFRB 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 PDGFRB 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-like transcriptional response. Phosphorylation of STAT3, STAT5, AKT and phospholipase Cγ 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-JAK2 signalling. Another tyrosine kinase inhibitor, imatinib, blocked signalling by the p.Val665Ala variant at a higher concentration compared with the wild-type 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 β compared with other characterized gain-of-function mutants, which may in part explain the particular set of symptoms associated with Penttinen syndrome.

Keywords: PDGFRB; Penttinen syndrome; STAT1; ageing; congenital disease; imatinib; platelet-derived growth factor; targeted therapy; tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acro-Osteolysis* / genetics
  • Aged
  • Humans
  • Interferons / metabolism
  • Limb Deformities, Congenital / genetics
  • Myofibromatosis* / genetics
  • Myofibromatosis* / metabolism
  • Progeria / genetics
  • Receptor, Platelet-Derived Growth Factor beta* / genetics
  • Receptor, Platelet-Derived Growth Factor beta* / metabolism
  • STAT1 Transcription Factor* / metabolism


  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interferons
  • PDGFRB protein, human
  • Receptor, Platelet-Derived Growth Factor beta

Supplementary concepts

  • Penttinen-Aula syndrome