Dataset Information

Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology.

ABSTRACT: 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 ?, and PDGFB, encoding PDGF-B, the specific ligand of PDGFR?, were found implicating the PDGF-B/PDGFR? 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 Mayo Clinic Florida Brain Bank 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? and two previously reported mutants, p.L658P and p.R987W PDGFR? in cell culture. We show that, in response to PDGF-BB stimulation, the p.L658P mutation completely suppresses PDGFR? 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.

SUBMITTER: Sanchez-Contreras M

PROVIDER: S-EPMC4107018 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology.

Sanchez-Contreras Monica M Baker Matthew C MC Finch NiCole A NA Nicholson Alexandra A Wojtas Aleksandra A Wszolek Zbigniew K ZK Ross Owen A OA Dickson Dennis W DW Rademakers Rosa R

Human mutation 20140603 8

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 PDGFRβ, were found implicating the PDGF-B/PDGFRβ 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 Mayo Clinic Florida Brain Bank with mode ...[more]

PMID: 24796542

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Project description:Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-R?. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-R? autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLC? activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb+/-;Pdgfrb+/- mice did not develop brain calcification, nor did Pdgfrbredeye/redeye mice, which show a 90% reduction of PDGFR? protein levels. In contrast, Pdgfbret/ret mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfbret/ret mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfbret/ret mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-R? signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.

Dataset Information

Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology.

Publications

Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology.

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