Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
At a glance
- Neurological disorders in 166 patients with basal ganglia calcification: a statistical evaluation. J. Neurol. 239, 36–38 (1992). , , &
- High frequency of calcification in basal ganglia on brain computed tomography images in Japanese older adults. Geriatr. Gerontol. Int. 13, 706–710 (2013). et al.
- Managing Idiopathic Basal Ganglia Calcification (“Fahr's Disease”) (Nova Science Publishers, New York, 2011).
- Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat. Genet. 44, 254–256 (2012). et al.
- Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 14, 11–22 (2013). et al.
- Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 80, 181–187 (2013). et al.
- Reporting a new mutation at the SLC20A2 gene in familial idiopathic basal ganglia calcification. Eur. J. Neurol. 20, e43–e44 (2013). , &
- Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification. PLoS ONE 8, e57060 (2013). , &
- Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 22, 1276–1312 (2008). , &
- Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8, 1875–1887 (1994). et al.
- Abnormal kidney development and hematological disorders in PDGF β–receptor mutant mice. Genes Dev. 8, 1888–1896 (1994).
- Pericyte loss and microaneurysm formation in PDGF-B–deficient mice. Science 277, 242–245 (1997). , , &
- Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055 (1999). , , , &
- Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003). et al.
- Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131, 1847–1857 (2004). et al.
- Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307–4316 (2002). et al.
- Additive effects of PDGF receptor β signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1, E52 (2003). , &
- Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010). , , &
- Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010). et al.
- Exclusion of linkage to chromosomes 14q, 2q37 and 8p21.1-q11.23 in a Serbian family with idiopathic basal ganglia calcification. J. Neurol. 258, 1637–1642 (2011). et al.
- Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. 79, 1283–1316 (1999). &
- Aberrant expression of platelet-derived growth factor A–chain cDNAs due to cryptic splicing of RNA transcripts in COS-1 cells. Nucleic Acids Res. 17, 6591–6601 (1989). , &
- Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev. 21, 316–331 (2007). et al.
- Severe vascular disturbance in a case of familial brain calcinosis. Acta Neuropathol. 109, 643–653 (2005). et al.
- Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11, 4131–4142 (2000). et al.
- Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. Am. J. Hum. Genet. 87, 354–364 (2010). et al.
- Thalamic calcification in vitamin D receptor knockout mice. Neuroreport 17, 717–721 (2006). et al.
- Interferon-γ induces progressive nigrostriatal degeneration and basal ganglia calcification. Nat. Neurosci. 14, 694–696 (2011). et al.
- Calcification of the basal ganglia in Down's syndrome and Alzheimer's disease. Acta Neuropathol. 76, 595–598 (1988).
- Similar calcification process in acute and chronic human brain pathologies. J. Neurosci. Res. 83, 147–156 (2006). et al.
- Parkinson's disease and basal ganglia calcifications: prevalence and clinico-radiological correlations. Clin. Neurol. Neurosurg. 94, 213–217 (1992). , , , &
- Extensive intracranial calcification secondary to hypoxia, presenting with dyspraxic gait. Australas. Radiol. 42, 232–233 (1998). &
- dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum. Mutat. 32, 894–899 (2011). , &
- Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput. Biol. 6, e1001025 (2010). et al.
- Tie2-Cre transgenic mice: a new model for endothelial cell–lineage analysis in vivo. Dev. Biol. 230, 230–242 (2001). et al.
- Fractionated manganese injections: effects on MRI contrast enhancement and physiological measures in C57BL/6 mice. NMR Biomed. 23, 913–921 (2010). et al.
- Supplementary Text and Figures (4,404 KB)
Supplementary Figures 1–3, Supplementary Tables 1–5 and Supplementary Note