Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions

Abstract

Ocular pterygium-digital keloid dysplasia (OPDKD) presents in childhood with ingrowth of vascularized connective tissue on the cornea leading to severely reduced vision. Later the patients develop keloids on digits but are other ways healthy. The overgrowth in OPDKD affects body parts that typically have lower temperature than 37°C. We present evidence that OPDKD is associated with a temperature sensitive, activating substitution, p.(Asn666Tyr), in PDGFRB. Phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts at 37°C but were further greatly increased at the average corneal temperature of 32°C. This suggest that the substitution cause significant constitutive autoactivation mainly at lower temperature. In contrast, a different substitution in the same codon, p.(Asn666Ser), is associated with Penttinen type of premature aging syndrome. This devastating condition is characterized by widespread tissue degeneration, including pronounced chronic ulcers and osteolytic resorption in distal limbs. In Penttinen syndrome fibroblasts, equal and high levels of phosphorylated PDGFRB was present at both 32°C and 37°C. This indicates that this substitution causes severe constitutive autoactivation of PDGFRB regardless of temperature. In line with this, most downstream targets were not affected by lower temperature. However, STAT1, important for tissue wasting, did show further increased phosphorylation at 32°C. Temperature-dependent autoactivation offers an explanation to the strikingly different clinical outcomes of substitutions in the Asn666 codon of PDGFRB.

Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome

“…A child with PS and KOS overlapping features with the Asn666His variant was treated by Pond et al, with rapid improvement of contractures and decrease of coarse facial features (Pond et al, 2018). In contrast, a patient with OPDKD did not respond to imatinib treatment, despite the PDGFRB variant (Asn666Tyr) being sensitive to treatment in vivo (Bredrup et al, 2021). More recently, a patient with PS (pVal665Ala, Patient 3 on Johnston et al) was also started on imatinib, with decreased hand pain, improved skin turgor, reduction of scars, and decreased conjunctival injection, only 2 months after initiating treatment (Wenger et al, 2020).…”

“…Pathogenic variants in PDGFRB, either constitutional or mosaic variants, have been linked to several disorders. Loss-of-function pathogenic variants cause idiopathic basal ganglia calcification type 4 syndrome (OMIM#615007) (Johnston et al, 2015) while heterozygous germ-line activating pathogenic variants are involved in several disorders: infantile myofibromatosis (OMIM#228550; Arg561Cys, Pro660Thr, Asn666Lys, Pro560Leu, and Lys567Glu) (Arts et al, 2017;Lepelletier et al, 2017;Murray et al, 2017), PS (OMIM#601812; Val665Ala, Asn666Ser), Kosaki overgrowth syndrome (KOS) (OMIM#616592; Pro584Arg, Trp566Arg) (Gawli nski et al, 2018;Minatogawa et al, 2017), Ocularpterygium-digital keloid dysplasia (OPDKD) (Asn666Tyr) (Bredrup et al, 2021) and in a patient with a combination of PS and KOS features (Asn666His) (Pond et al, 2018). In addition, postzygotic (mosaic) activating pathogenic variants have also been described: a man with segmental overgrowth, atrophic skin and multiple intra and extracranial fusiform aneurysms (Karasozen et al, 2019) and a patient with infantile myofibromatosis and some PS and KOS-related features (Guimier et al, 2019).…”

“…Gain of function pathogenic variants promote the active conformation of PDGFR in the absence of its ligand, resulting in constitutive activation of downstream signaling pathways (Arts et al, 2017). Several activating pathogenic variants in PDGRFB are sensitive to receptor tyrosine kinase (RTK) inhibitors in vitro (Abarca et al, 2014;Arts et al, 2017;Bredrup et al, 2021Bredrup et al, , 2019Pond et al, 2018;Wenger et al, 2020) and in vivo (Martignetti et al, 2013;Pond et al, 2018;Wenger et al, 2020), with variable results. In patients with infantile myofibromatosis, clear and rapid reduction in size of myofibromas has been observed (Mudry et al, 2017;Wenger et al, 2020).…”

First case report of Penttinen syndrome from India

“…Bredrup et al recently demonstrated that the phosphorylation of STAT1, a downstream target of PDGFRB‐mediating tissue wasting, was increased at 32°C compared to 37°C in fibroblasts from patients with p.Asn666Ser Penttinen syndrome. They postulated that the increased PDGFRB‐STAT1 signaling at lower temperature peripheral body sites could explain the severe skin ulceration and tissue degenerative changes seen in Penttinen syndrome (Bredrup et al, 2021). Although speculative, this temperature sensitive activation of PDGFRB‐STAT1 signaling could offer a possible explanation for the milder phenotype seen in our patient, as the patient lives in an area with a significantly warmer climate than the other reported cases.…”

A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

“…This rare autosomal dominant hereditary disease is characterized by corneal vascularization leading to visual impairment early in life. Most patients also develop keloids on fingers and toes but are otherwise healthy [4][5][6]. We recently described two families presenting with OPDKD [4,6].…”