PDGFRB mutations cause infantile myofibromatosis and other human congenital diseases

Activating mutations in platelet-derived growth factor receptors (PDGFRα and β) have been found in different types of cancers. Increased PDGF signaling has also been linked to fibrotic diseases. When I started to work on this topic, no functionally significant point mutation in PDGFRβ had been described. However, in the past few years, germline and somatic point mutations in PDGFRB, the gene encoding PDGFRβ, were identified in different human congenital diseases. These mutations had not been characterized at the beginning of our study. The first goal of our study was to characterize novel PDGFRβ mutations associated with Fahr disease, familial infantile myofibromatosis (IM), overgrowth and Penttinen syndrome. We also wanted to understand how germline mutations in the same gene could give rise to such different phenotypes. Interestingly, our results showed that most of the PDGFRβ mutations have an impact on the kinase activity of the receptor. Indeed, in Fahr disease, a neurological disorder characterized by brain calcification, germline PDGFRβ point mutations induce a total or partial loss of receptor signaling. In the three other pathologies, the germline PDGFRB mutations are gain-of-function. Moreover, we showed that these three activating mutations had three different profiles. Indeed, we found differences in their level of activation, their level of expression and the signaling pathways that were activated downstream of them. We concluded that these differences could account for the different phenotypes associated with each mutation. Another goal of our project was to investigate if sporadic cases of IM, which are much more frequent than the familial form, were also linked to mutations in PDGFRB. We found recurrent and novel activating mutations in this gene, allowing a deeper understanding of the disease. Our results also highlight the hypothesis of a double-hit model to explain the development of sporadic and familial IM. Finally, we demonstrated that all these activated mutants found in distinct pathologies were sensitive to tyrosine kinase inhibitors. We even demonstrated in one patient that this type of inhibitors could be used efficiently in children to treat a PDGFRB mutation-associated disease. In conclusion, our findings shed light on the mechanism of poorly understood diseases. They also suggest a treatment for patients carrying gain-of-function PDGFRβ mutations in these pathologies.