Abstract
Four different amino acid substitutions have been reported at the p.Asn666 position in platelet-derived growth factor receptor β (PDGFRβ): p.Asn666Lys, p.Asn666Tyr, p.Asn666Ser, and p.Asn666His. All four substitutions result in strikingly different phenotypes, ranging from somatic infantile myofibromatosis in p.Asn666Lys and ocular pterygium-digital keloid dysplasia in p.Asn666Tyr to a severe form of Penttinen syndrome in p.Asn666Ser, while p.Asn666His is associated with a complex phenotype characterized by debilitating hand and foot contractures and facial coarseness. Here, we show that the p.Asn666Lys, p.Asn666Tyr, and p.Asn666His substitutions result in increased total PDGFRβ phosphorylation at 32°C compared to 37°C. All four substitutions exhibit distinct activation patterns of specific PDGFRβ tyrosine residues at both temperatures, indicating a unique activation of each variant. The temperature effect on downstream signaling is present across all substitutions, resulting in substitution-specific downstream signaling at both 37°C and 32°C. This complex interplay of downstream signaling proteins could be important for the clinical manifestations of p.Asn666 PDGFRB variants. Furthermore, variant-specific overactivation of tyrosine residues and downstream signaling at 32°C emphasize the importance of temperature as an environmental factor in the pathogenesis of this diverse group of disorders.
Keywords:
PDGFRB; germline activating mutations; receptor tyrosine kinase; temperature sensitivity; thermokinetics.