title: SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification.
abstract: Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/- mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA.
authors.forename: Mary Catherine
authors.initials: MC
authors.lastname: Wallingford
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA.
authors.forename: Jia Jun
authors.initials: JJ
authors.lastname: Chia
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Leaf
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA.|Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA.
authors.forename: Suhaib
authors.initials: S
authors.lastname: Borgeia
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Chavkin
authors.affiliation: Department of Pharmacology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Chenphop
authors.initials: C
authors.lastname: Sawangmake
authors.affiliation: Department of Radiology, University of Washington, Seattle, WA.
authors.forename: Ken
authors.initials: K
authors.lastname: Marro
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA.|Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cox
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA.
authors.forename: Mei Y
authors.initials: MY
authors.lastname: Speer
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Giachelli
mesh_terms: D000818:Animals; D001160:Arterioles / Q000473:pathology*; D001480:Basal Ganglia Diseases / Q000134:cerebrospinal fluid / Q000473:pathology*; D002114:Calcinosis / Q000134:cerebrospinal fluid / Q000473:pathology*; D002386:Cataract / Q000235:genetics; D002831:Choroid Plexus / Q000378:metabolism; D004805:Ependyma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008850:Microphthalmos / Q000235:genetics; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid / Q000473:pathology*; D059906:Neuroimaging; D010710:Phosphates / Q000134:cerebrospinal fluid* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D009419:Nerve Tissue Proteins; D010710:Phosphates; D034741:RNA, Small Interfering; C493565:Slc20a2 protein, mouse; D050611:Sodium-Phosphate Cotransporter Proteins, Type III
keywords: Slc20a2; cerebral vascular calcification; cerebrospinal fluid; glymphatic spaces; idiopathic basal ganglia calcification; phosphate
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