Objective: This study aims to investigate the expression level of reported PDGFB mutations in human cerebral microvascular endothelial cells (hCMEC/D3), and further propose a potential gain-of-function (GOF) molecular mechanism underlying PDGFB-mediated primary brain calcification (PBC) pathogenesis.

Background: PDGFB is well established as a key pathogenic gene in PBC, but the underlying molecular mechanism remains incompletely understood. While early studies proposed that PDGFB loss-of-function (LOF) mediated by blood brain barrier (BBB) dysfunction contributed to pathogenesis, recent evidence indicates that elevated PDGFB levels may drives brain calcification. This process is likely regulated by the upregulated expression of RUNX2 in pericytes and SLC20A1 on the surface of astrocytes, suggesting that a GOF pathway may underlie PDGFB‑driven PBC.

Method: Based on the finding that cerebral vascular endothelial cells are implicated in PDGFB mutation-induced PBC, the hCMEC/D3 cell was selected to explore the underlying molecular mechanisms. We collected all PDGFB exon mutations validated by familial co-segregation and the sporadic PDGFB mutations identified by our team. Plasmids carrying these mutations as well as the ret mutation, all tagged with V5, were constructed and transfected into hCMEC/D3 cells, and Western Blot was subsequently performed to detect the protein levels of PDGFB in the cell lysates.

Results: We collated seven PDGFB mutations (p.M1I [1], p.L9P [2], p.R78C [3], p.L119P [2], p.P122L [4], p.Q145* [2] and p.*242Yext*89 [2,5]) as well as the clinical information of patients in the pedigree corresponding to each mutation [table1] [6]. Additionally, four sporadic PDGFB point mutations (p.C79R, p.N136S, p.T171M and p.R217Q) were identified by our team. Among the mutations tested, L119P, the ret mutation, and *242Yext*89 showed significantly increased PDGFB protein expression compared to wild-type. Several other mutations, including R78C, C79R, P122L, and N136S, also exhibited a trend toward elevated expression [figure1].

Conclusion: Several pathogenic PDGFB mutations lead to increased PDGFB protein levels in endothelial cells, supporting a GOF mechanism in the pathogenesis of PDGFB‑driven PBC. These findings challenge the traditional LOF model and point to elevated PDGFB dosage as a potential driver of brain calcification.

PDGFB Exon Mutations and Clinical Information

Western Blot Results of PDGFB Mutant Protein

References: 1. Biancheri R, Severino M, Robbiano A, et al. White matter involvement in a family with a novel PDGFB mutation. Neurol Genet. 2016;2(3):e77. doi:10.1212/NXG.0000000000000077
2. Keller A, Westenberger A, Sobrido MJ, et al. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet. 2013;45(9):1077-1082. doi:10.1038/ng.2723
3. Wang C, Ma X, Xu X, et al. A PDGFB mutation causes paroxysmal nonkinesigenic dyskinesia with brain calcification. Movement Disorders. 2017;32(7):1104-1106. doi:10.1002/mds.26988
4. Keogh MJ, Pyle A, Daud D, et al. Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB. Neurology. 2015;84(17):1818-1820. doi:10.1212/WNL.0000000000001517
5. The French PFBC study group, Ramos EM, Carecchio M, et al. Primary brain calcification: an international study reporting novel variants and associated phenotypes. Eur J Hum Genet. 2018;26(10):1462-1477. doi:10.1038/s41431-018-0185-4
6. Yektay Farahmand M, Wasselius J, Englund E, Braverman I, Puschmann A, Ilinca A. Small vessel disease in primary familial brain calcification with novel truncating PDGFB variants. Neurol Neurochir Pol. 2024;58(1):94-105. doi:10.5603/pjnns.97716

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pdgfb-mutations-may-induce-primary-brain-calcification-via-the-gain-of-function-mechanism/