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.
Highlights
Idiopathic basal ganglia calcification (IBGC), called Fahr disease, is a rare neurological disease characterized by symmetrical bilateral calcifications, which are mostly located in the basal ganglia but can be detected in other areas of the brain
We demonstrated that the PDGFRB mutations that have been identified in IBGC lead to a partial or complete loss of function
Our results showed that the L658P substitution completely abolished PDGFRb activity
Summary
Idiopathic basal ganglia calcification (IBGC), called Fahr disease, is a rare neurological disease characterized by symmetrical bilateral calcifications, which are mostly located in the basal ganglia but can be detected in other areas of the brain. Mice deficient in SLC20A2 show brain calcification, indicating a causal relationship between SLC20A2 mutations and the human disease [7]. Mutations were found in PDGFB, which encodes platelet-derived growth factor B [8]. They were not characterized experimentally, these mutations were predicted to represent loss-of-function alleles. In mice carrying a viable PDGFB hypomorph allele, Keller and colleagues observed blood brain barrier abnormalities and brain calcification, which were reminiscent of human IBGC [8]. We have observed that platelet-derived growth factor (PDGF)-B increases the expression of SLC20A2 in mesenchymal cell cultures, providing a possible link between these two genes in IBGC [11]
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