ArticleEuropean journal of human genetics : EJHG2019
A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome.
Article in European journal of human genetics : EJHG, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 31 citations in OpenAlex.
- Loss of ATRAID in Late-Onset, Non-Syndromic Retinitis Pigmentosa.Investigative ophthalmology & visual science · 2026Article
- On subcellular distribution of the zinc finger 469 protein (ZNF469) and observed discrepancy in the localization of endogenous and overexpressed ZNF469.FEBS open bio · 2025Article
- Temperature as a Key Modulator: Investigating Phosphorylation Patterns of p.Asn666Human mutation · 2025Article
- Defining the progeria phenome.Aging · 2024Article
- Corneal Vascularization Associated With a Novel PDGFRB Variant.Investigative ophthalmology & visual science · 2023Article
- Lipodystrophy-associated progeroid syndromes.Hormones (Athens, Greece) · 2022Review
- Penttinen syndrome-associated PDGFRB Val665Ala variant causes aberrant constitutive STAT1 signalling.Journal of cellular and molecular medicine · 2022Article
- Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy.Signal transduction and targeted therapy · 2022Review
- Skeletal stem cell fate defects caused by Pdgfrb activating mutation.Development (Cambridge, England) · 2021Article
- PDGF receptor mutations in human diseases.Cellular and molecular life sciences : CMLS · 2021Review
- Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions.Human molecular genetics · 2021Article
- Molecular mechanisms underlying nuchal hump formation in dolphin cichlid, Cyrtocara moorii.Scientific reports · 2019Article
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13 authors at 4 institutions in 2 countries.
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Abstract
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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