title: Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling.
abstract: Platelet-derived growth factors (PDGF) bind to two related receptor tyrosine kinases, which are encoded by the PDGFRA and PDGFRB genes. Recently, heterozygous PDGFRB mutations have been described in patients diagnosed with idiopathic basal ganglia calcification (IBGC or Fahr disease), a rare inherited neurological disorder. The goal of the present study was to determine whether these mutations had a positive or negative impact on the PDGFRB activity. We first showed that the E1071V mutant behaved like wild-type PDGFRB and may represent a polymorphism unrelated to IBGC. In contrast, the L658P mutant had no kinase activity and failed to activate any of the pathways normally stimulated by PDGF. The R987W mutant activated Akt and MAP kinases but did not induce the phosphorylation of signal transducer and activator of transcription 3 (STAT3) after PDGF stimulation. Phosphorylation of phospholipase Cγ was also decreased. Finally, we showed that the R987W mutant was more rapidly degraded upon PDGF binding compared to wild-type PDGFRB. In conclusion, PDGFRB mutations associated with IBGC impair the receptor signalling. PDGFRB loss of function in IBGC is consistent with recently described inactivating mutations in the PDGF-B ligand. These results raise concerns about the long-term safety of PDGF receptor inhibition by drugs such as imatinib.
authors.affiliation: De Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Florence A
authors.initials: FA
authors.lastname: Arts
authors.forename: Amélie I
authors.initials: AI
authors.lastname: Velghe
authors.forename: Monique
authors.initials: M
authors.lastname: Stevens
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Ahmed
authors.initials: A
authors.lastname: Essaghir
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
mesh_terms: D019943:Amino Acid Substitution; D001480:Basal Ganglia Diseases / Q000235:genetics*; D002114:Calcinosis / Q000235:genetics*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D051966:Phospholipase C gamma / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D051966:Phospholipase C gamma
keywords: Fahr disease; PDGFRB; STAT3; brain calcification; imatinib; receptor degradation