Kaitsun Yeung
Research Mentor(s): Qing Li
Mentor Department: Medicine Division of Hematology & Oncology
Authors:
Session: Session 4 (1:00pm – 1:50pm)
Presentation Type: Poster 88
Abstract
Primary familial brain calcification, also known as familial idiopathic basal ganglia calcification and Fahr’s disease, is an inherited neurological disorder characterized by abnormal calcium deposition in basal ganglia. Clinically, this condition manifest as parkinsonism, dystonia, involuntary movements, and psychiatric symptoms. A few causative genes associated with primary familial brain calcification has been identified which include SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2 genes. 37 year old male was referred to genetics clinic due to basal ganglia calcification identified during his evaluation for dystonia. Molecular testing of the proband identified a variant of uncertain significance in PDGFB gene denoted c.725A>G (p.242Trpext89). Familial segregation study identified a same variant in his mother who was also noted to have significant basal ganglia calcification despite the lack of dystonia. This variant disrupts the translational stop codon, leading to a PDGF-BB protein elongated by 89 amino acids which has never been reported. The PDGFB gene encodes PDGF-BB which is a critical ligand for vascular integrity and pericyte function. We hypothesize that this alteration may impair ligand-receptor interactions or disrupt PDGFRß signaling pathway, which regulates blood-brain barrier (BBB) maintenance and vascular calcification prevention. Aberrant signaling may compromise pericyte survival and function, leading to BBB disruption and calcium-phosphate deposition in brain vasculature. Aberrant ERK/RUNX2 signaling has been implicated in vascular calcification, while astrocyte and microglial interactions may exacerbate mineralization and neuroinflammation. Understanding the functional impact of the novel PDGFB variant identified in this proband may provide insights into basal ganglia calcification. Understanding the molecular mechanism due to aberrant PDGFRß signaling will allow us to develop therapeutic strategies to target the PDGFRß pathway, order to potentially mitigate vascular calcification and its associated neurodegenerative symptoms.
