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Genetic Screening and Functional Characterization of PDGFRB Mutations Associated with Basal Ganglia Calcification of Unknown Etiology
Author(s) -
SanchezContreras Monica,
Baker Matthew C.,
Finch NiCole A.,
Nicholson Alexandra,
Wojtas Aleksandra,
Wszolek Zbigniew K.,
Ross Owen A.,
Dickson Dennis W.,
Rademakers Rosa
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22582
Subject(s) - pdgfrb , pdgfb , biology , autophosphorylation , cancer research , pdgfra , mutation , calcification , genetics , platelet derived growth factor receptor , pathology , receptor , kinase , medicine , gene , growth factor , protein kinase a , gist , stromal cell
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 .