Distinct functional classes of PDGFRB pathogenic variants in primary familial brain calcification

Area of Science:

• Neurogenetics
• Molecular Biology
• Cell Signaling

Background:

• Primary familial brain calcification (PFBC) is an inherited neurological disorder.
• Platelet-derived growth factor receptor beta (PDGFRB) gene variants are associated with PFBC.
• Previous studies suggested some PDGFRB variants reduce receptor activity, but functional data was limited.

Purpose of the Study:

• To comprehensively analyze the molecular mechanisms of PDGFRB variants linked to PFBC.
• To assess the impact of these variants on receptor expression, signaling, and function.
• To correlate molecular findings with clinical data for improved genetic counseling.

Main Methods:

• Transfection of mutated PDGFRB receptors into cell lines.
• Assays to monitor receptor expression, tyrosine kinase activity, ligand binding, and mitogenic signaling.
• Integration of clinical, genetic, and molecular data for variant classification.

Main Results:

• Four PDGFRB mutants exhibited a complete loss of tyrosine kinase activity.
• One novel variant (p.Pro154Ser) reduced receptor expression and abolished PDGF-BB binding.
• Other variants showed partial loss of function due to reduced expression or signaling.
• Nine variants were classified as pathogenic or likely pathogenic.

Conclusions:

• PDGFRB variants associated with PFBC lead to a loss of receptor function through distinct molecular mechanisms.
• Understanding these mechanisms is crucial for explaining incomplete penetrance and neurological symptoms.
• This research provides valuable insights for genetic counseling in PFBC patients and families.