Genetic Screening and Functional Characterization of PDGFRB Mutations Associated with Basal Ganglia Calcification of Unknown Etiology

Three causal genes for idiopathic basal ganglia calcification ( IBGC ) have been identified. Most recently, mutations in PDGFRB , encoding a member of the platelet‐derived growth factor receptor family type β, and PDGFB , encoding PDGF ‐ B , the specific ligand of PDGFR β, were found implicating the PDGF ‐ B / PDGFR β pathway in abnormal brain calcification. In this study, we aimed to identify and study mutations in PDGFRB and PDGFB in a series of 26 patients from the M ayo C linic F lorida B rain B ank with moderate to severe basal ganglia calcification ( BCG ) of unknown etiology. No mutations in PDGFB were found. However, we identified one mutation in PDGFRB , p.R695C located in the tyrosine kinase domain, in one BGC patient. We further studied the function of p.R695C mutant PDGFR β and two previously reported mutants, p.L658P and p.R987W PDGFR β in cell culture. We show that, in response to PDGF ‐ BB stimulation, the p.L658P mutation completely suppresses PDGFR β autophosphorylation, whereas the p.R695C mutation results in partial loss of autophosphorylation. For the p.R987W mutation, our data suggest a different mechanism involving reduced protein levels. These genetic and functional studies provide the first insight into the pathogenic mechanisms associated with PDGFRB mutations and provide further support for a pathogenic role of PDGFRB mutations in BGC .