Temperature as a Key Modulator: Investigating Phosphorylation Patterns of p.Asn666 Variants and Their Role in Downstream Signaling.
(2025) Human Mutation — Vol. 2025, n° 2025, p. 6664372 (2025)
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- Authors
Gladkauskas, Titas 
Cristea, Ileana Mehrasa, Roya Bredrup, Cecilie
- Abstract
- Four different amino acid substitutions have been reported at the p.Asn666 position in platelet-derived growth factor receptor (PDGFR): 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 PDGFR phosphorylation at 32°C compared to 37°C. All four substitutions exhibit distinct activation patterns of specific PDGFR 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 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.
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Citations
Gladkauskas, T., Cristea, I., Mehrasa, R., Demoulin, J. B., Gjertsen, B. T., Bruland, O., Rødahl, E., & Bredrup, C. (2025). Temperature as a Key Modulator: Investigating Phosphorylation Patterns of p.Asn666 Variants and Their Role in Downstream Signaling. Human Mutation, 2025(2025), 6664372. https://doi.org/10.1155/humu/6664372 (Original work published 2025)