Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of
Monica Sanchez-Contreras1, Matthew C Baker, NiCole A Finch
1Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
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 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 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 PDGFRβ and two previously reported mutants, p.L658P and p.R987W PDGFRβ in cell culture. We show that, in response to PDGF-BB stimulation, the p.L658P mutation completely suppresses PDGFRβ 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.
Insights
Mutations in the PDGFRB gene are linked to basal ganglia calcification (BGC). This study identified a new PDGFRB mutation and analyzed its functional impact, supporting its role in BGC pathogenesis.
Area of Science:
- Neurogenetics
- Molecular Biology
- Biochemistry
Background:
- Idiopathic basal ganglia calcification (BGC) is a neurological disorder.
- Previous studies identified mutations in PDGFRB and PDGFB, implicating the PDGF-B/PDGFRβ pathway in BGC.
- The precise pathogenic mechanisms of PDGFRB mutations in BGC remain unclear.
Purpose of the Study:
- To identify and functionally characterize mutations in PDGFRB and PDGFB in patients with BGC.
- To elucidate the pathogenic mechanisms underlying PDGFRB-associated BGC.
Main Methods:
- Genetic screening of PDGFRB and PDGFB in 26 BGC patients.
- Functional analysis of identified PDGFRB mutations (p.R695C, p.L658P, p.R987W) in cell culture.
- Assessment of PDGFRβ autophosphorylation and protein levels in response to PDGF-BB stimulation.
Main Results:
- No PDGFB mutations were detected.
- One novel PDGFRB mutation (p.R695C) was identified in a BGC patient.
- Functional studies revealed differential impacts of PDGFRB mutations on autophosphorylation and protein stability, suggesting distinct pathogenic mechanisms.
Conclusions:
- PDGFRB mutations play a pathogenic role in BGC.
- The study provides novel insights into the molecular mechanisms of PDGFRB-associated BGC.
- Further research into the PDGF-B/PDGFRβ pathway is warranted for understanding and potentially treating BGC.
