Affinage

SLC20A2

Sodium-dependent phosphate transporter 2 · UniProt Q08357

Length
652 aa
Mass
70.4 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC20A2 encodes PiT-2, a sodium-dependent inorganic phosphate (Pi) transporter that serves as the principal mediator of phosphate import in the central nervous system and participates in Pi sensing, signaling, and homeostasis across multiple tissues. PiT-2 adopts a 12-transmembrane topology with its minimal transport unit mapped to the N- and C-terminal regions containing conserved PD-domain residues (Asp28, Asp506, Ser113, Glu55, Glu575, His502) essential for Na⁺-coupled Pi translocation, while the large intracellular loop7 controls AMPK/AKT-dependent plasma membrane trafficking and mediates a transport-independent interaction with MAP1B that promotes neuronal outgrowth (PMID:11356966, PMID:15184021, PMID:16790504, PMID:21586110, PMID:29259219, PMID:35713844). PiT-2 forms Pi-regulated homo-oligomers and PiT-1/PiT-2 hetero-oligomers that sense extracellular Pi independently of transport to activate ERK1/2 signaling, regulates FGF23 secretion from bone, couples to XPR1-mediated Pi efflux through inositol pyrophosphates to maintain intracellular Pi balance, and protects vascular smooth muscle cells from calcification via osteoprotegerin (PMID:11932396, PMID:29233890, PMID:29551636, PMID:32393577, PMID:30041812). Loss-of-function mutations in SLC20A2 cause primary familial brain calcification (PFBC/IBGC), with Slc20a2-knockout mice recapitulating elevated CSF phosphate and progressive basal ganglia calcification; astrocyte-specific deletion and rescue establish astrocytic PiT-2 as the critical cell-autonomous mediator of brain Pi clearance, and splice-switching antisense oligonucleotides targeting intronic variants restore SLC20A2 function and suppress calcification in humanized mouse models (PMID:23934451, PMID:26660102, PMID:39019040, PMID:39121859).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Establishing that PiT-2 activity is post-translationally regulated by extracellular Pi and PKCε, and that it physically associates with actin, revealed that PiT-2 is not a constitutive transporter but a dynamically regulated membrane protein whose surface distribution depends on cytoskeletal organization.

    Evidence Isotopic Pi uptake, retroviral interference, co-IP of PiT-2/actin, pharmacological and antisense PKCε perturbation in mammalian cells

    PMID:10066763 PMID:10196273

    Open questions at the time
    • Direct PKCε phosphorylation sites on PiT-2 not identified
    • Mechanism linking actin to PiT-2 redistribution not defined at molecular level
  2. 2001 High

    Determining the 12-transmembrane topology of PiT-2 with extracellular N- and C-termini provided the structural framework needed to interpret all subsequent mutagenesis, domain-function, and virus-binding studies.

    Evidence Glycosylation mapping at Asn81, epitope tagging, cell-free translation with microsomal insertion of truncation mutants

    PMID:11356966

    Open questions at the time
    • No high-resolution 3D structure
    • Topology model relies on biochemical inference rather than crystallography
  3. 2002 High

    Discovery that PiT-2 forms homo-oligomers whose conformation changes with extracellular Pi — independently of transport — introduced the concept that PiT-2 functions as a Pi sensor in addition to a transporter.

    Evidence Chemical cross-linking and co-IP of differentially tagged PiT-2 molecules with Pi titration

    PMID:11932396

    Open questions at the time
    • Stoichiometry of oligomer not determined
    • Signaling consequences of conformational change not yet identified at this point
  4. 2004 High

    Mutagenesis of conserved PD-domain serines and identification of ECD1 as the amphotropic MuLV binding domain dissected transport from receptor function, proving these are mechanistically separable activities of PiT-2.

    Evidence Site-directed mutagenesis with Pi uptake and retroviral binding/infection assays; PiT-1/PiT-2 chimeric receptors

    PMID:14694091 PMID:15184021

    Open questions at the time
    • Structural basis for uncoupling of Pi binding from translocation not resolved
    • Whether transport-independent sensing uses the same Pi-binding site remained unclear
  5. 2006 High

    Characterization of PiT-2 transport kinetics — positive cooperativity, Na⁺-independent transport at acidic pH, and decoupled Na⁺ leak — established that PiT-2 is not a simple symporter but has complex ion-coupling properties, with Glu55 and Glu575 linking Na⁺ to Pi transport.

    Evidence ³²Pi and ²²Na⁺ tracer uptake in Xenopus oocytes expressing wild-type and mutant PiT-2

    PMID:16790504

    Open questions at the time
    • Electrogenicity and stoichiometry under physiological conditions not fully resolved
    • Structural basis for cooperativity unknown
  6. 2008 High

    Localization of PiT-2 to the apical brush-border membrane of renal proximal tubule with dietary Pi-dependent protein regulation established PiT-2 as a physiologically regulated renal Pi transporter distinct from NaPi-IIa.

    Evidence Western blot of brush-border fractions and immunohistochemistry of rat kidney under varied dietary Pi

    PMID:19073637

    Open questions at the time
    • Mechanism of dietary regulation (transcriptional vs. post-translational) not distinguished
    • Relative contribution to total renal Pi reabsorption vs. NaPi-IIa/IIc not quantified
  7. 2011 High

    Mapping the minimal transport unit to the N- and C-terminal ~350 residues — with the large intracellular domain dispensable — revealed a modular architecture separating transport from regulatory/scaffolding functions.

    Evidence Systematic deletion mutagenesis with ³²Pi uptake in Xenopus oocytes

    PMID:21586110

    Open questions at the time
    • How the dispensable intracellular domain contributes to regulation in vivo not addressed
  8. 2013 High

    Demonstration that Slc20a2 knockout in mice causes thalamic and basal ganglia calcification, and that PiT-2 can substitute for PiT-1 in VSMC phosphate uptake and calcification, established PiT-2 as both necessary for brain Pi homeostasis and partially redundant with PiT-1 in vascular cells.

    Evidence Slc20a2 global KO mice with histological analysis; VSMC-specific PiT-1 KO with PiT-2 siRNA and overexpression

    PMID:23934451 PMID:23968976

    Open questions at the time
    • Cell type responsible for brain calcification not yet identified
    • Why PiT-1 cannot compensate in brain unclear
  9. 2015 High

    Finding elevated CSF Pi in Slc20a2-KO mice directly linked brain calcification to impaired phosphate clearance from the CSF compartment, establishing the pathophysiological mechanism.

    Evidence CSF Pi measurement in Slc20a2-KO vs. wild-type mice

    PMID:26660102

    Open questions at the time
    • Which cell types clear CSF Pi not yet resolved
    • Whether calcification results solely from elevated Pi or involves additional factors
  10. 2016 High

    Haploinsufficient mouse models, regulatory enhancer deletion, dominant-negative mutations, and vitamin D-responsive transcription collectively revealed that PFBC arises from quantitative reduction in PiT-2 function through diverse mechanisms — coding mutations, trafficking defects, regulatory element loss, and dominant-negative oligomerization — with a transport activity threshold determining disease onset.

    Evidence Slc20a2+/- mice with micro-CT and CSF Pi; CRISPR enhancer deletion; co-expression of PFBC variants in KO cells; CRISPR SLC20A2 KD with calcification assay; patient fibroblast localization studies

    PMID:26822507 PMID:27184385 PMID:27943094 PMID:28722801 PMID:32506582

    Open questions at the time
    • Precise transport threshold for disease not quantified in vivo
    • Whether dominant-negative effect occurs for all oligomeric variants unknown
  11. 2017 High

    Discovery that PiT-1/PiT-2 heterodimerization mediates Pi sensing via ERK1/2 independently of transport, and that loop7 controls trafficking via MAP1B interaction and promotes neurite outgrowth, separated PiT-2's signaling/scaffolding roles from its transporter function.

    Evidence BRET and cross-linking for heterodimerization; transport-deficient mutant rescue of ERK1/2; co-IP of loop7/MAP1B-LC1 with neurite outgrowth assay in Neuro2A; Drosophila NMJ analysis

    PMID:29233890 PMID:29259219

    Open questions at the time
    • Structural basis of heterodimerization interface unknown
    • Whether MAP1B interaction occurs in vivo in mammalian brain neurons not confirmed
    • Downstream signaling cascade from ERK1/2 to target gene regulation in skeletal cells incompletely defined
  12. 2018 High

    Linking PiT-2 to FGF23 regulation in bone and to osteoprotegerin-dependent VSMC protection placed PiT-2 at the intersection of systemic phosphate endocrinology and local vascular defense, extending its role beyond transport to hormonal and paracrine signaling.

    Evidence PiT-2 KO mice with dietary Pi perturbation and ex vivo bone shaft FGF23 assay; PiT-2 heterozygous KO with CKD model and osteoprotegerin rescue

    PMID:29551636 PMID:30041812

    Open questions at the time
    • Molecular mechanism linking PiT-2 sensing to FGF23 transcription/secretion unknown
    • Whether osteoprotegerin regulation is direct or indirect not established
  13. 2020 High

    Demonstration that PiT-2 functionally couples to XPR1-mediated Pi efflux via inositol pyrophosphates established a bidirectional import-efflux circuit that maintains intracellular Pi and ATP homeostasis; meanwhile, skeletal muscle and intestinal conditional KOs revealed tissue-specific roles in energy metabolism and hormonal adaptation to low Pi.

    Evidence SLC20A2 overexpression/depletion with XPR1 KO cells, IP6K inhibitor, Pi flux measurements; HSA-Cre skeletal muscle double KO; Villin-Cre intestinal Pit-2 KO with dietary Pi restriction

    PMID:32080237 PMID:32393577 PMID:32564464

    Open questions at the time
    • Physical interaction between PiT-2 and XPR1 not demonstrated
    • How PP-IP levels are communicated between influx and efflux machinery is unclear
    • Whether skeletal muscle phenotype is transport-dependent or sensing-dependent not fully distinguished
  14. 2022 Medium

    Identification of AMPK/AKT-mediated phosphorylation of loop7 as a trafficking switch, and observation of Golgi disruption, impaired autophagy, and mitochondrial damage in PFBC patient iPSC-derived neurons and astrocytes, began to connect Pi imbalance to intracellular organelle dysfunction.

    Evidence Cell-surface biotinylation with kinase inhibitors for loop7 phosphorylation; iPSC-derived neurons/astrocytes with organelle and apoptosis markers

    PMID:35713844 PMID:36584480

    Open questions at the time
    • Specific phosphorylation sites on loop7 mediating AMPK vs. AKT effects not fully mapped
    • Organelle dysfunction findings in iPSC cells lack rescue controls
    • Whether organelle phenotypes are primary or secondary to Pi imbalance unknown
  15. 2024 High

    Cell-type resolution was achieved: astrocyte-specific PiT-2 was identified as the critical mediator of brain Pi clearance (with polarized PiT-2/XPR1 distribution enabling directional transport), MYORG was placed as a facilitator of astrocytic PiT-2 function, and intronic splice-variant correction by ASOs rescued calcification in humanized mice — establishing a therapeutic paradigm.

    Evidence Astrocyte-specific Pit2 conditional KO and viral re-expression rescue; immunofluorescence for polarized PiT-2/XPR1; minigene splicing assay with ASO treatment in patient cells and ICV delivery in humanized KI mice

    PMID:39019040 PMID:39121859

    Open questions at the time
    • Whether ASO therapy reverses existing calcification or only prevents new deposition unclear
    • MYORG's mechanism of PiT-2 facilitation not defined at molecular level
    • Long-term safety and efficacy of CNS-directed ASO in humans unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of PiT-2, the molecular basis of PiT-1/PiT-2 heterodimerization and its signaling specificity, whether PiT-2's transport-independent neuronal functions contribute to PFBC pathology, and whether therapeutic restoration of PiT-2 can reverse established brain calcification.
  • No atomic-resolution structure of any PiT family member
  • Transport-independent neuronal branching role not tested in PFBC context
  • In vivo demonstration of calcification reversal lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 1
Pathway
R-HSA-382551 Transport of small molecules 6 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2
Partners
MAP1BMYORGPRKCESLC20A1XPR1
Complex memberships
PiT-1/PiT-2 hetero-oligomerPiT-2 homo-oligomer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PiT-2 has a 12-transmembrane domain topology with extracellular N- and C-terminal extremities, established by glycosylation mapping (Asn81), epitope tagging, and cell-free translation/microsomal insertion assays of C-terminal truncation mutants. Glycosylation mapping, epitope tagging, cell-free translation with microsomal membrane insertion, immunoprecipitation Journal of virology High 11356966
1999 PiT-2-mediated phosphate uptake and retrovirus entry are inversely regulated by extracellular phosphate concentration via posttranslational modifications of cell-surface PiT-2, not changes in cell-surface abundance; a physical association of PiT-2 with actin was demonstrated, and actin network organisation controls PiT-2 surface distribution and internalization upon virus binding. Cell-surface expression assay, phosphate uptake assay, retrovirus infection assay, co-immunoprecipitation (PiT-2/actin), actin perturbation with cytochalasin D and LPA Journal of virology High 10196273
2002 PiT-2 forms homo-oligomeric assemblies at the cell surface whose conformation changes in response to extracellular inorganic phosphate concentration, demonstrated by cross-linking, detergent-resistant co-immunoprecipitation of differentially tagged molecules, and correlation with phosphate uptake and virus susceptibility. Chemical cross-linking, co-immunoprecipitation of differentially epitope-tagged PiT-2, TFA treatment to preserve only covalent bonds Journal of virology High 11932396
2004 Mutation of the conserved serine in each of the two PD001131 homology domains of human PiT-2 abolishes phosphate transport but preserves virus receptor function; cross-linking shows that phosphate-induced structural changes in PiT-2 cell-surface oligomers occur independently of the transport cycle, indicating that ion binding (not translocation) drives conformational change. Site-directed mutagenesis, phosphate uptake assay, retrovirus infection assay, chemical cross-linking of transport-deficient mutants Journal of molecular biology High 15184021
2005 Conserved aspartates Asp28 and Asp506 in the N- and C-terminal PiT family signature sequences (consensus GANDVANA) of human PiT-2 are individually essential for Na+-dependent phosphate transport; mutation of either to asparagine abolishes transport while preserving retroviral receptor function, indicating proper protein folding. Evolutionary sequence logo analysis, site-directed mutagenesis, 32Pi uptake in Xenopus oocytes, retroviral receptor infection assay The FEBS journal High 15955065
2006 Human PiT-2 exhibits positive cooperativity in phosphate uptake (K0.5 ~164 µM), supports Na+-independent phosphate transport at acidic pH, and Na+ is transported by PiT-2 even without phosphate, demonstrating decoupling of Na+ from Pi transport; putative transmembrane residues Glu55 and Glu575 link Pi import to Na+ transport. 32Pi uptake assay in Xenopus oocytes, 22Na+ uptake assay, Pi transport knockout mutant analysis American journal of physiology. Cell physiology High 16790504
2011 The minimal Pi-transporting unit of human PiT-2 maps to its N-terminal (~182 aa) and C-terminal (~170 aa) regions; the large intracellular domain and two predicted TM domains are dispensable for transport. Conserved His502 (C-terminal signature) and the PiT1 equivalent Glu70 are critical for Pi transport function. Deletion mutagenesis, 32Pi uptake in Xenopus oocytes, retroviral receptor infection assay as folding control BMC biochemistry High 21586110
1999 Protein kinase C epsilon (PKCε) specifically upregulates PiT-2-mediated Na/Pi uptake; activation by PMA is blocked by amphotropic MuLV infection (which occupies PiT-2) but not by GALV infection (which uses PiT-1), and is abolished by PKCε-selective antisense oligonucleotides or by the pan-PKC inhibitor bisindolylmaleimide but not by the conventional PKC inhibitor Gö 6976. Isotopic Na/Pi uptake assay, PKC isoform overexpression, isoform-selective antisense oligonucleotides, retroviral interference assay The Journal of biological chemistry High 10066763
2000 Upon amphotropic MuLV infection, PiT-2 is redistributed from the plasma membrane to a cytosolic punctate compartment distinct from Golgi, ER, endosomes, lysosomes, and mitochondria, co-localizing with intracellular virus; this redistribution is specific to A-MuLV/PiT-2 interaction and underlies superinfection resistance. Confocal laser scanning microscopy of GFP- and epitope-tagged PiT-2, Western blotting, phosphate uptake assay Journal of virology High 10684301
2004 Extracellular domain 1 (ECD1) of human PiT-2 is required for amphotropic MuLV binding and infection, identified using a 12-TM topology model and an A-MuLV receptor-binding assay that distinguishes binding from post-binding steps. PiT1-PiT2 chimeric receptor constructs, A-MuLV receptor binding assay, infection assay in CHO cells Journal of virology High 14694091
2008 PiT-2/SLC20A2 is localized to the brush-border membrane (apical membrane) of rat renal proximal tubule epithelia and its protein abundance is regulated by dietary phosphate: decreased on high-Pi diet and increased on low-Pi diet, with a slower adaptive time course than NaPi-IIa. Western blot of brush-border membrane fractions, immunohistochemistry of kidney slices, dietary Pi manipulation American journal of physiology. Renal physiology High 19073637
2013 PiT-2/SLC20A2 can mediate phosphate uptake and phosphate-induced calcification of vascular smooth muscle cells (VSMCs) in the absence of PiT-1, demonstrating redundant roles; PiT-2 knockdown reduced phosphate uptake and calcification in PiT-1-deficient VSMCs, and PiT-2 overexpression restored these in human PiT-1-deficient VSMCs. VSMC-specific PiT-1 knockout mice, siRNA knockdown of PiT-2, PiT-2 overexpression, Na-dependent phosphate uptake assay, matrix calcification assay Arteriosclerosis, thrombosis, and vascular biology High 23968976
2013 Knockout of Slc20a2 in mice causes calcifications in thalamus, basal ganglia, and cortex, demonstrating that loss of PiT-2 alone is sufficient to cause brain calcification. Slc20a2 knockout mouse model, histological analysis Journal of molecular neuroscience : MN High 23934451
2015 Slc20a2-knockout mice have elevated inorganic phosphate (Pi) levels in cerebrospinal fluid (CSF), consistent with a role of PiT-2 in Pi export from the CSF compartment. CSF Pi measurement in Slc20a2-KO vs. wild-type mice Neurogenetics High 26660102
2016 Slc20a2 is expressed in choroid plexus, ependyma, and arteriolar smooth muscle cells in mouse brain; Slc20a2+/- haploinsufficient mice develop age-dependent basal ganglia calcification in glymphatic pathway-associated arterioles, accompanied by elevated CSF phosphate and hydrocephalus; siRNA knockdown in smooth muscle cells increases susceptibility to high-phosphate-induced calcification. Slc20a2+/- mouse model, micro-CT, immunohistochemistry, CSF Pi measurement, siRNA knockdown of Slc20a2 in SMCs, in vitro calcification assay Brain pathology High 26822507
2017 PiT1 and PiT2 form high-abundance homodimers and Pi-regulated low-abundance heterodimers at the cell surface; Pi-regulated PiT1-PiT2 heterodimerization mediates Pi sensing independently of Pi uptake, requiring Pi binding at conserved residues Ser113 (PiT2) and Ser128 (PiT1); deletion of either PiT blunts Pi-dependent ERK1/2 phosphorylation and target gene upregulation in skeletal cells, rescued by transport-deficient PiT mutants. Cross-linking, bioluminescence resonance energy transfer (BRET), Pi transport-deficient mutants, ERK1/2 phosphorylation assay, gene expression analysis in PiT KO cells The Journal of biological chemistry High 29233890
2018 PiT2/Slc20a2 is required for appropriate Pi-dependent secretion of FGF23; PiT2 KO mice show abnormally normal intact FGF23 levels on low-Pi diet, and ex vivo isolated long bone shafts from PiT2 KO mice fail to show Pi-dependent regulation of Fgf23 secretion independently of systemic endocrine loops. PiT2 KO mouse model, Pi-modified diets, serum iFGF23/cFGF23 measurement, ex vivo isolated long bone shaft assay Molecular metabolism High 29551636
2018 PiT-2 haploinsufficiency in vascular smooth muscle cells decreases sodium-dependent phosphate uptake, increases phosphate-induced calcification, and reduces osteoprotegerin levels; osteoprotegerin supplementation attenuates the excess calcification, placing PiT-2 upstream of osteoprotegerin in the phosphate-induced VSMC calcification pathway. Global PiT-2 heterozygous KO mouse model, chronic kidney disease + high-phosphate diet model, micro-CT, phosphate uptake assay, osteoprotegerin ELISA and supplementation Kidney international High 30041812
2020 SLC20A2 and XPR1 functionally interact to regulate cellular phosphate homeostasis: SLC20A2 overexpression increases both phosphate uptake and XPR1-mediated phosphate efflux; SLC20A2 depletion strongly decreases XPR1-mediated efflux; this cross-talk depends on inositol pyrophosphates (PP-IPs) via XPR1's IP-binding pocket and IP6K1/2 activity, maintaining constant intracellular Pi and ATP levels. SLC20A2 overexpression/siRNA depletion, XPR1 KO cells, phosphate uptake and efflux assays, IP6K inhibitor treatment, XPR1 PP-IP-binding pocket mutants The Journal of biological chemistry High 32393577
2016 PFBC-associated SLC20A2 missense variants (e.g., PiT2D28N, PiT2E575K) can act in a dominant-negative manner in mammalian cells, reducing wild-type PiT-2 Pi transport beyond simple haploinsufficiency, as shown by co-expression in Slc20a2-/- mouse cells. Co-expression of WT and variant PiT2 in Slc20a2-/- mouse cells, Pi uptake assay Journal of molecular neuroscience : MN Medium 27943094
2017 The large intracellular loop7 of PiT-2 is necessary for trafficking of PiT-2 to the cell surface and for neurite outgrowth; loop7 interacts with microtubule-associated protein 1B light chain 1 (MAP1B-LC1), and mutations in the MAP1B-binding site impair neurite outgrowth independently of Pi transport function. PiT-2 truncation and mutagenesis, cell surface trafficking assay, co-immunoprecipitation (PiT-2 loop7/MAP1B-LC1), neurite outgrowth assay in Neuro2A cells, Drosophila NMJ analysis of dPiT/Futsch interaction Scientific reports Medium 29259219
2022 Missense mutations in PiT-2 loop7 (p.T390A, p.S434W) decrease Pi transport and cell-surface levels of PiT-2 by impairing AMPK- or AKT-mediated phosphorylation of loop7, while PD-domain mutations (p.S121C, p.S601W) impair substrate-binding without affecting phosphorylation, identifying phosphorylation-regulated membrane localization as a distinct regulatory mechanism. Stable cell lines expressing PiT-2 variants, Pi uptake assay, cell-surface biotinylation, AMPK/AKT phosphorylation analysis, kinase inhibitor treatment Neuroscience bulletin Medium 35713844
2016 Calcitriol (vitamin D receptor agonist) selectively upregulates SLC20A2 expression and reduces calcification in vitro; CRISPR-mediated knockdown of SLC20A2 abrogates vitamin D-mediated inhibition of calcification, placing SLC20A2 downstream of vitamin D receptor signaling in suppression of calcification. RT-qPCR, Alizarin Red calcification assay, CRISPR-mediated SLC20A2 knockdown in SaOs-2 cells Scientific reports Medium 27184385
2024 In astrocytes, PiT-2 (importer) is distributed over entire astrocyte processes while XPR1 (exporter) localises to astrocyte end-feet on blood vessels; this polarized distribution enables directional phosphate transport for brain Pi homeostasis; astrocyte-specific Pit2 KO elevates brain Pi and causes calcification, and astrocyte-specific PiT-2 re-expression in Pit2-KO mice suppresses brain calcification; PFBC-associated galactosidase MYORG facilitates PiT-2-dependent Pi uptake in astrocytes. Astrocyte-specific conditional KO mice, immunofluorescence localization, Pi homeostasis assays, astrocyte-specific viral re-expression rescue experiment Neuron High 39019040
2024 Intronic variants in SLC20A2 cause aberrant splicing by altering binding affinity of splicing machinery to cryptic exons, leading to premature termination; splice-switching antisense oligonucleotides (ASOs) restore functional SLC20A2 expression in patient cells and, after intracerebroventricular delivery to humanized SLC20A2-KI mice, reduce CSF Pi levels and suppress brain calcification. Minigene splicing assay, ASO treatment of patient cells, SLC20A2 humanized knock-in mice, ICV ASO administration, CSF Pi measurement, brain calcification scoring Neuron High 39121859
2019 Seven novel SLC20A2 missense mutations identified in PFBC patients show impaired phosphate transport activity in functional assays, and partial preservation of Pi transport (27.8% of WT in c.680C>T variant) may be insufficient to cause IBGC, suggesting a transport activity threshold for disease onset. Stable cell lines expressing SLC20A2 variants, Pi uptake assay, cell membrane localization assay Scientific reports Medium 31754123
2017 A PFBC-associated SLC20A2 duplication (p.Trp626_Thr629dup) does not reduce PiT-2 protein expression but alters its subcellular localization and reduces Pi uptake in patient primary fibroblasts, distinguishing a localization/trafficking defect from expression loss as a disease mechanism. Primary fibroblasts from PFBC patient, immunofluorescence subcellular localization, Pi uptake assay Journal of cellular physiology Medium 28722801
2020 Simultaneous deletion of both Slc20a1 (PiT-1) and Slc20a2 (PiT-2) in skeletal muscle causes atrophy and death by postnatal day 13; single or three-allele knockouts reduce running activity in a gene-dose dependent manner; mechanistically, loss is associated with reduced ERK1/2 activation and elevated AMP kinase activity consistent with energy stress; C2C12 cells show reduced oxygen consumption dependent on both Pi transport and ERK1/2 signaling. Skeletal muscle-specific conditional double KO mice (HSA-Cre), running activity measurement, grip strength, ERK1/2/AMPK phosphorylation assays, oxygen consumption rate in C2C12 myoblasts Scientific reports High 32080237
2024 Slc20a2 (PiT-2) promotes hippocampal neuronal branching and survival independently of its phosphate transport function; PiT-1 instead promotes synaptic plasticity via a likely Otoferlin-dependent regulation of synaptic vesicle trafficking affecting the GABAergic system, as shown by electrophysiological and molecular analyses in conditional KO mice. Conditional KO mice, electrophysiology, molecular analyses, behavioral testing (hippocampal-dependent learning/memory) Cell death & disease Medium 38195526
2020 Intestinal epithelial-specific deletion of Pit-2 does not impair systemic phosphate homeostasis under normal dietary conditions but causes exaggerated hypercalciuria and sustained elevation of 1,25(OH)2 vitamin D3 upon dietary phosphate restriction, revealing a role in modulating hormonal responses to low phosphate. Villin-Cre × floxed Pit-2 conditional KO mice, dietary Pi restriction, serum/urine electrolyte measurement, hormone assays, intestinal phosphate transport assay Acta physiologica High 32564464
2018 Global PiT-2 knockout mice show reduced bone mineral density and length in mandible, femur, and tibia, with reductions in both cortical and trabecular thickness, demonstrating a required role of PiT-2 in normal bone development and growth. Global PiT-2 homozygous KO mice, micro-CT analysis, histomorphometry Biochemical and biophysical research communications Medium 29133259
2019 SLC20A2 variants cause loss of Pi transport function in endothelial cells differentiated from IBGC patient-derived iPSCs, without altering differentiation capacity or expression of other SLC20 members, demonstrating cell-autonomous phosphate transport deficiency in disease-relevant endothelial cells. Patient-derived iPSC differentiation to endothelial cells, Flp-In CHO stable expression of variant proteins, Pi uptake assay Biochemical and biophysical research communications Medium 30704756
2022 Dysfunctional PiT-2 in iPSC-derived neurons and astrocytes from PFBC patients causes disrupted Golgi structure, impaired autophagy with increased mTOR activity, mitochondrial damage, and increased apoptosis, linking cellular Pi imbalance to multiple organelle dysfunction pathways in disease-relevant cell types. iPSC differentiation to neurons and astrocytes, Golgi morphology assay, autophagy markers, mTOR activity, mitochondrial analysis, apoptosis assay Biochemical and biophysical research communications Medium 36584480
2016 A deletion 35 kb upstream of SLC20A2 that removes a putative enhancer reduces SLC20A2 mRNA to ~60% of normal (equivalent to coding loss-of-function alleles) and reduces Pi uptake by ~39%; CRISPR deletion of this enhancer in HEK293 cells reproduces the ~40% mRNA reduction, demonstrating enhancer-mediated regulation of SLC20A2 expression. RT-ddPCR, ex vivo Pi uptake assay on patient blood cells, CRISPR-Cas9 enhancer deletion in HEK293 cells Movement disorders High 32506582

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Compatibility in the Ustilago maydis-maize interaction requires inhibition of host cysteine proteases by the fungal effector Pit2. PLoS pathogens 206 23459172
2008 The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. American journal of physiology. Renal physiology 135 19073637
2013 Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 122 23334463
2013 Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arteriosclerosis, thrombosis, and vascular biology 111 23968976
1988 Complete amino acid sequence of p453-plasmid-mediated PIT-2 beta-lactamase (SHV-1). The Biochemical journal 94 3260490
2017 Phosphate (Pi)-regulated heterodimerization of the high-affinity sodium-dependent Pi transporters PiT1/Slc20a1 and PiT2/Slc20a2 underlies extracellular Pi sensing independently of Pi uptake. The Journal of biological chemistry 90 29233890
2015 Brain calcification process and phenotypes according to age and sex: Lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 86 26129893
2013 Loss of function of Slc20a2 associated with familial idiopathic Basal Ganglia calcification in humans causes brain calcifications in mice. Journal of molecular neuroscience : MN 85 23934451
2018 Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2. Molecular metabolism 70 29551636
2014 Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan. Neurology 70 24463626
2016 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. Brain pathology (Zurich, Switzerland) 63 26822507
1997 Three distinct envelope domains, variably present in subgroup B feline leukemia virus recombinants, mediate Pit1 and Pit2 receptor recognition. Journal of virology 61 9343161
2020 Interplay between primary familial brain calcification-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis. The Journal of biological chemistry 60 32393577
2009 Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency. American journal of physiology. Renal physiology 59 19493963
2013 SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia. Neurogenetics 58 24135862
2001 Transmembrane topology of PiT-2, a phosphate transporter-retrovirus receptor. Journal of virology 56 11356966
1998 RNA levels of human retrovirus receptors Pit1 and Pit2 do not correlate with infectibility by three retroviral vector pseudotypes. Human gene therapy 56 9853528
2009 Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis. Pflugers Archiv : European journal of physiology 54 19841935
2015 Slc20a2 is critical for maintaining a physiologic inorganic phosphate level in cerebrospinal fluid. Neurogenetics 51 26660102
2013 Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification. PloS one 49 23437308
2015 Familial idiopathic basal ganglia calcification: Histopathologic features of an autopsied patient with an SLC20A2 mutation. Neuropathology : official journal of the Japanese Society of Neuropathology 48 26635128
2011 Mapping of the minimal inorganic phosphate transporting unit of human PiT2 suggests a structure universal to PiT-related proteins from all kingdoms of life. BMC biochemistry 46 21586110
2018 PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. Kidney international 45 30041812
2016 The type III transporters (PiT-1 and PiT-2) are the major sodium-dependent phosphate transporters in the mice and human brains. Brain research 45 26923164
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