A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib

Pond, Dinel; Arts, Florence A; Mendelsohn, Nancy J.; Demoulin, Jean‐Baptiste; Scharer, Gunter; Messinger, Yoav

doi:10.1038/gim.2017.104

Cited by 51 publications

(75 citation statements)

References 29 publications

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“…Functional studies on patient fibroblasts, as well as transduced HeLa and cells, showed that Asn666Ser caused constitutive tyrosine kinase activation, like previously found for other Penttinen-syndrome associated variants ( Fig. 3) [12,16].…”

Section: Discussionsupporting

confidence: 78%

“…The phenotypic spectrum seen in patients with different missense variants in PDGFRB range from basal ganglia calcifications, infantile myofibromatosis and premature aging to somatic overgrowth with neurologic deterioration [6][7][8][9][10][11][12][13][14]16]. The basal ganglia calcification-related Leu658Pro and Arg987Trp substitutions were found to abolish kinase activity (Leu658Pro) or destabilise PDGFRβ (Arg987Trp) [22].…”

Section: Discussionmentioning

confidence: 99%

“…So far, PDGFRB is the only of the two PDGF receptors where variants have been linked to congenital disease. Missense variants in PDGFRB have been associated with idiopathic basal ganglia calcifications (OMIM#615007; Leu658Pro and Arg987Trp) [6], infantile myofibromatosis (OMIM#228550; Arg561Cys, Pro660Thr and Asn666Lys) [7][8][9], Penttinen-type premature aging syndrome (OMIM#601812; Val665Ala) [10][11][12], Kosaki overgrowth syndrome (OMIM#616592; Pro584Arg and Trp566Arg) [13][14][15], and was recently found (Asn666His) in a single patient with Penttinen-overlapping features (hemangioma, craniosynostosis, intracranial cysts, gingival hypertrophy, acro-osteolysis, contractures and carpal tunnel syndrome) [16]. PDGFR targeted tyrosine kinase inhibitor treatment has been effective in two patients with germline activating PDGFRB variants; one a Penttinen-syndrome like patient with Asn666His [16], the other a child with infantile myofibromatosis and germline Arg681Cys [17].…”

Section: Introductionmentioning

confidence: 99%

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A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome

et al. 2018

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Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-β, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p.(Asn666Ser) variants in two patients with lipodystrophy, acro-osteolysis and severely reduced vision due to corneal neovascularisation, reminiscent of a severe form of Penttinen syndrome with more pronounced connective tissue destruction. In line with this phenotype, patient skin fibroblasts were prone to apoptosis. Both in patient fibroblasts and stably transduced HeLa and HEK293 cells, autophosphorylation of PDGFRβ was observed, as well as increased phosphorylation of downstream signalling proteins such as STAT1, PLCγ1, PTPN11/SHP2-Tyr580 and AKT. Phosphorylation of MAPK3 (ERK1) and PTPN11/SHP2-Tyr542 appeared unaffected. This suggests that this missense change not only weakens tyrosine kinase autoinhibition, but also influences substrate binding, as both PTPN11 tyrosines (Tyr542 and Tyr580) usually are phosphorylated upon PDGFR activation. Imatinib was a strong inhibitor of phosphorylation of all these targets, suggesting an option for precision medicine based treatment.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome

et al. 2018

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“…Platelet‐derived growth factor receptor beta (PDGFRB) is a mitogen for cells of mesenchymal origin, including smooth muscle cells . Recently, PDGFRB mutations were reported in myofibromas and myofibromatosis . Recurrent driver events are yet to be reported in odontogenic myxoma .…”

Section: Introductionmentioning

confidence: 99%

“…12 Recently, PDGFRB mutations were reported in myofibromas and myofibromatosis. [13][14][15][16][17][18][19] Recurrent driver events are yet to be reported in odontogenic myxoma. [20][21][22][23] Considering that the odontogenic myxoma cells can show myofibroblastic differentiation 3,4 and myxoid areas are eventually present in myofibroma, 24,25 we raised the hypothesis whether these tumors share a common molecular profile.…”

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confidence: 99%

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas

Siqueira

Sousa

Carlos³

et al. 2020

J Oral Pathology Medicine

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Background The molecular pathogenesis of odontogenic myxoma has not been established yet. Considering that odontogenic myxoma may show myofibroblastic differentiation and myxoid areas can be observed in intra‐osseous myofibromas, we tested the hypothesis whether both tumors share a common molecular profile. As recent studies have reported PDGFRB recurrent driver mutations in myofibroma, we evaluated PDGFRB mutations in odontogenic myxomas. Methods A convenience sample of 15 odontogenic myxomas cases was selected. We direct sequenced PDGFRB exons 12 and 14, where p.R561C (c.1681C>T) and p.N666K (c.1998C>G) hotspot mutations have been reported among others in single and/or multiple myofibromas. Results All 15 odontogenic myxoma samples were successfully sequenced, and all 15 had wild‐type sequences for the PDGFRB mutations investigated. Conclusion Our findings suggest that PDGFRB mutations do not play a role in odontogenic myxoma pathogenesis, which might be helpful in the differential diagnosis of challenging cases.

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Association of PDGFRB Mutations With Pediatric Myofibroma and Myofibromatosis

et al. 2019

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IMPORTANCE Myofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease.OBJECTIVE To determine the frequency, spectrum, and clinical implications of mutations in the PDGFRB receptor tyrosine kinase found in sporadic myofibroma and myofibromatosis. DESIGN, SETTING, AND PARTICIPANTSIn this retrospective study of 69 patients with sporadic myofibroma or myofibromatosis, 85 tumor samples were obtained and analyzed by targeted deep sequencing of PDGFRB. Mutations were confirmed by an alternative method of sequencing and were experimentally characterized to confirm gain of function and sensitivity to the tyrosine kinase inhibitor imatinib. MAIN OUTCOMES AND MEASURESFrequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally. RESULTSOf the 69 patients with tumor samples (mean [SD] age, 7.8 [12.7] years), 60 were children (87%; 29 girls [48%]) and 9 were adults (13%; 4 women [44%]). Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. Mutations were particularly associated with severe multicentric disease (13 of 19 myofibromatosis cases [68%]). Although patients had no familial history, 3 of 25 mutations (12%) were likely to be germline, suggesting de novo heritable alterations. All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations.CONCLUSIONS AND RELEVANCE Gain-of-function mutations of PDGFRB in myofibromas may affect only children and be more frequent in the multicentric form of disease, albeit present in solitary pediatric myofibromas. These alterations may be sensitive to tyrosine kinase inhibitors. The PDGFRB sequencing appears to have a high value for diagnosis, prognosis, and therapy of soft-tissue tumors in children.

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A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib

Cited by 51 publications

References 29 publications

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas

Association of PDGFRB Mutations With Pediatric Myofibroma and Myofibromatosis

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