PDGFB – Idiopathic Basal Ganglia Calcification

Idiopathic basal ganglia calcification (IBGC), also known as primary familial brain calcification (PFBC), is a rare autosomal dominant disorder marked by bilateral calcium deposits in the basal ganglia and diverse neurologic and psychiatric manifestations such as dystonia, cognitive impairment, and hallucinations. The disease is genetically heterogeneous, with pathogenic variants in SLC20A2, PDGFRB, and PDGFB disrupting phosphate homeostasis and blood–brain barrier integrity.

Multiple case reports establish PDGFB as a causative gene for IBGC. A de novo nonsense variant, c.439C>T (p.Gln147Ter), was identified in a 20-year-old woman presenting with laryngeal dystonia and cerebral calcification, absent in both parents’ DNA ([PMID:24518837]). A Japanese family carrying the recurrent stop variant c.445C>T (p.Arg149Ter) showed segregation in a father–son pair with auditory hallucinations and basal ganglia calcifications ([PMID:25211641]). A novel PDGFB mutation was detected in a 62-year-old woman and her asymptomatic younger son with mild calcification, underscoring variable expressivity ([PMID:35750946]).

In cohort studies, PDGFB pathogenic variants are rare but recurrent. In a Chinese screen of 192 PFBC patients, one nonsense (c.220G>T, p.Glu74Ter) and two missense (c.232C>T, p.Arg78Cys; c.610C>A, p.Pro204Thr) variants were identified in sporadic cases with absent controls ([PMID:27984190]). Exome analyses and copy-number assays have also uncovered splice-site changes and partial gene deletions, confirming loss-of-function as the primary mechanism.

Functional assays corroborate that PDGFB haploinsufficiency drives calcification. Patient-derived iPS-endothelial cells with splice and frameshift variants (e.g., c.457-1G>T; c.33_34delCT) secrete 34.0% of normal PDGF-BB in serum and 58.6% in culture media, reflecting impaired ligand production ([PMID:30952898]). In mice, altered PDGF-B distribution in Pdgfb^ret/ret models leads to pericyte loss, blood–brain barrier disruption, and pericapillary calcifications, faithfully mirroring the human phenotype ([PMID:26599395]).

No studies have refuted PDGFB’s role in IBGC, and there is consistent concordance between genetic and experimental data. Overall, the evidence supports a Strong gene–disease relationship, with multiple LoF variants in unrelated probands and two independent familial segregations across three cohorts.

Key Take-home: Heterozygous loss-of-function variants in PDGFB cause autosomal dominant IBGC through PDGF-B deficiency and blood–brain barrier compromise, enabling precise molecular diagnosis and guiding family counseling.

References

• European journal of human genetics : EJHG • 2014 • A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia PMID:24518837
• Psychiatry and clinical neurosciences • 2015 • First Japanese family with primary familial brain calcification due to a mutation in the PDGFB gene: an exome analysis study PMID:25211641
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2022 • Primary familial brain calcification with mild phenotype due to a new PDGFB mutation PMID:35750946
• Gene • 2016 • Mutation screening of PDGFB gene in Chinese population with primary familial brain calcification PMID:27984190
• Scientific reports • 2019 • Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells PMID:30952898
• PloS One • 2015 • Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification PMID:26599395

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