Affinage

SLC20A2

Sodium-dependent phosphate transporter 2 · UniProt Q08357

Length
652 aa
Mass
70.4 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC20A2 (PiT-2) is a Na+-dependent inorganic phosphate (Pi) importer that maintains cellular and extracellular Pi homeostasis across diverse tissues and underlies primary familial brain calcification (PMID:16790504, PMID:23934451, PMID:39121859). It adopts a 12-transmembrane topology with extracellular N- and C-termini, in which conserved aspartates Asp28 and Asp506 and conserved PD-domain serines are individually required for Na+-coupled Pi transport while overall folding and retroviral receptor function are preserved (PMID:11356966, PMID:15955065, PMID:15184021); the N- and C-terminal transmembrane backbone, including His502 in the C-terminal signature sequence, constitutes the minimal transporting unit, and putative residues E55/E575 couple Pi import to Na+ flux (PMID:16790504, PMID:21586110). PiT-2 assembles into Pi-regulated cell-surface oligomers whose conformation reorganizes in response to extracellular Pi independently of transport (PMID:11932396, PMID:15184021), and Pi-regulated PiT1–PiT2 heterodimerization functions as an extracellular phosphate sensor that drives ERK1/2 phosphorylation independently of Pi uptake, with Ser-113 required for heterodimerization (PMID:29233890). Beyond transport, PiT-2 surface trafficking is governed by AMPK/AKT-mediated phosphorylation of its intracellular loop7, and loop7 binds MAP1B light chain 1 to promote neurite outgrowth and neuronal branching independently of phosphate transport (PMID:29259219, PMID:35713844, PMID:38195526). PiT-2 cooperates with the Pi exporter XPR1 in an inositol-pyrophosphate (PP-IP)–dependent import–export axis, and in astrocytes process-localized PiT2 and end-feet–localized XPR1 establish directional Pi handling that maintains brain Pi homeostasis (PMID:32393577, PMID:39019040). PiT-2 also acts as a Pi sensor regulating FGF23 secretion in bone and contributes to phosphate-induced vascular calcification of smooth muscle cells (PMID:23968976, PMID:29551636). Loss or haploinsufficiency of Slc20a2 in mice elevates CSF Pi and produces age-dependent basal ganglia and vascular calcification, recapitulating human SLC20A2-linked primary familial brain calcification, which is caused by loss-of-function, dominant-negative, mislocalizing, and aberrant-splicing variants (PMID:23934451, PMID:26660102, PMID:26822507, PMID:27943094, PMID:39121859).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 High

    Establishing the membrane topology was prerequisite to mapping which residues face the extracellular space and which form the transport machinery.

    Evidence Glycosylation mapping, epitope tagging, and cell-free translation/microsomal truncation assays

    PMID:11356966

    Open questions at the time
    • Topology alone does not identify the ion-coupling or substrate-binding residues
    • No high-resolution structure of the transporter
  2. 2006 High

    Defining the transport kinetics and ion-coupling clarified that PiT2 couples Na+ to Pi import but can decouple Na+ flux, distinguishing it functionally from PiT1.

    Evidence 32Pi and 22Na+ uptake assays in Xenopus oocytes with transport-knockout mutants

    PMID:16790504

    Open questions at the time
    • Structural basis of cooperativity not resolved
    • Physiological relevance of Na+-independent acidic-pH transport untested in vivo
  3. 2011 High

    Mutagenesis of conserved aspartates, serines, and the minimal transporting backbone localized the catalytic determinants of Pi transport while showing folding/receptor function is separable from transport.

    Evidence Site-directed and deletion mutagenesis with Pi uptake and retroviral receptor controls in oocytes/CHO cells

    PMID:15184021 PMID:15955065 PMID:21586110

    Open questions at the time
    • No atomic structure assigning these residues to a transport pathway
    • Functional role of the dispensable large internal loop not fully defined
  4. 2004 High

    Cross-linking showed that extracellular Pi reorganizes surface PiT2 oligomers even in transport-dead mutants, separating Pi sensing/conformational change from the transport cycle itself.

    Evidence Chemical cross-linking, reciprocal co-IP of tagged molecules, transport-deficient mutants in living cells

    PMID:11932396 PMID:15184021

    Open questions at the time
    • Molecular trigger of the conformational change not defined at residue level
    • Downstream consequence of oligomer reorganization unclear at the time
  5. 2000 High

    Linking transport regulation to actin association, PKCepsilon signaling, and virus-induced redistribution revealed posttranslational control of surface PiT2 activity beyond abundance changes.

    Evidence Co-IP with actin, PKC isotype gain/loss-of-function, confocal imaging, retrovirus interference assays

    PMID:10066763 PMID:10196273 PMID:10684301

    Open questions at the time
    • Direct actin/PiT2 interaction interface not mapped
    • Physiological relevance of viral-receptor biology to phosphate homeostasis unclear
  6. 2008 Medium

    Localizing PiT2 to renal proximal tubule brush-border and showing dietary-Pi regulation implicated it in physiological phosphate handling.

    Evidence Western blot and immunohistochemistry of rat kidney under defined dietary Pi

    PMID:19073637

    Open questions at the time
    • Quantitative contribution to renal Pi reabsorption versus NaPi-IIa not established
    • No genetic test of renal-specific function here
  7. 2013 High

    Knockout mouse studies established that reduced PiT2 alone causes brain calcification and that PiT2 can drive VSMC phosphate uptake and calcification redundantly with PiT1.

    Evidence Slc20a2 KO mouse histology; VSMC-specific PiT1 KO with PiT2 knockdown/overexpression rescue and calcification assays

    PMID:23934451 PMID:23968976

    Open questions at the time
    • Cell-of-origin of brain calcification not yet resolved in 2013
    • Link between transport defect and calcification mechanism not yet mechanistic
  8. 2016 High

    CSF Pi measurements and haploinsufficient/expression studies tied PiT2 loss to elevated CSF phosphate and glymphatic-arteriolar calcification, and identified calcitriol-driven SLC20A2 as protective against calcification.

    Evidence CSF Pi colorimetry in KO mice, Slc20a2+/- mouse model with micro-CT, choroid plexus/ependyma immunostaining, CRISPR knockdown in SaOs-2 with calcification assay

    PMID:26660102 PMID:26822507 PMID:27184385

    Open questions at the time
    • Direction of PiT2 Pi flux at choroid plexus (import vs net export role) not directly resolved
    • Mechanism linking CSF Pi elevation to focal calcification incomplete
  9. 2017 High

    Identifying Pi-regulated PiT1–PiT2 heterodimerization as a transport-independent ERK1/2-activating phosphate sensor reframed PiT2 as a signaling receptor, and loop7–MAP1B binding defined a transport-independent neuronal function.

    Evidence BRET, cross-linking, KO cells, Ser-113 mutagenesis, ERK assays; Co-IP with MAP1B-LC1, transport-dead mutants, neurite outgrowth in Neuro2A

    PMID:29233890 PMID:29259219

    Open questions at the time
    • Structural basis of the Pi-regulated heterodimer interface unresolved
    • Downstream transcriptional targets of ERK1/2 sensing not fully cataloged
  10. 2018 Medium

    Ex vivo bone and VSMC studies showed PiT2 acts as an endocrine Pi sensor controlling FGF23 secretion and protects against vascular calcification partly via osteoprotegerin.

    Evidence PiT2 KO mice with dietary Pi modulation, ex vivo bone shaft FGF23 secretion assay; heterozygous KO VSMCs with OPG measurement and supplementation

    PMID:29551636 PMID:30041812

    Open questions at the time
    • Sensing mechanism upstream of FGF23 not molecularly defined
    • Whether OPG regulation is transport-dependent unresolved
  11. 2020 High

    The SLC20A2–XPR1 PP-IP–dependent import/export axis and dual transport/ERK1/2 sensing in muscle defined how PiT2 integrates cellular Pi flux with metabolic signaling.

    Evidence Pi uptake/efflux assays with SLC20A2/XPR1 manipulation and IP6K inactivation; skeletal-muscle conditional double KO with ERK1/2 and AMPK signaling and respirometry

    PMID:32080237 PMID:32393577

    Open questions at the time
    • Physical coupling between SLC20A2 and XPR1 (direct vs metabolite-mediated) not fully defined
    • PP-IP sensor identity for the uptake side not pinpointed
  12. 2024 High

    Cell-type-specific genetics and therapeutic intervention defined polarized astrocytic PiT2/XPR1 Pi handling, transport-independent neuronal branching roles, and antisense correction of splicing variants as a disease-modifying strategy.

    Evidence Astrocyte- and hippocampus-specific conditional KO with rescue, immunofluorescence, MYORG co-analysis; minigene splicing assays and ICV ASO in humanized SLC20A2-KI mice

    PMID:38195526 PMID:39019040 PMID:39121859

    Open questions at the time
    • How MYORG facilitates PiT2-mediated Pi uptake mechanistically is undefined
    • Generalizability of ASO correction across diverse SLC20A2 variant classes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the transport function, oligomeric Pi-sensing/ERK1/2 signaling, and loop7-dependent trafficking/MAP1B interaction are integrated into the tissue-specific calcification and cognitive phenotypes remains incompletely resolved.
  • No atomic-resolution structure of human PiT2 or its PiT1/XPR1 complexes
  • Mechanism converting elevated extracellular/CSF Pi into focal calcification not fully defined
  • Relative in vivo contribution of transport-dependent vs transport-independent functions to disease unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0001618 virus receptor activity 2 GO:0008092 cytoskeletal protein binding 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
ACTBMAP1BMYORGPRKCESLC20A1XPR1
Complex memberships
PiT1-PiT2 heterodimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PiT-2 (SLC20A2) has 12 transmembrane domains with extracellular N- and C-terminal extremities, as determined by comprehensive topology mapping including glycosylation of asparagine 81, epitope tagging of termini, and orientation of C-terminal truncation mutants in cell-free translation/microsomal membrane assays. Epitope tagging, glycosylation mapping, cell-free translation with microsomal membrane incorporation, immunoprecipitation of truncation mutants Journal of virology High 11356966
2005 Conserved aspartates Asp28 (N-terminal signature sequence) and Asp506 (C-terminal signature sequence) of human PiT2 are individually critical for Na+-dependent phosphate transport function; alanine/asparagine substitutions abolish transport while retroviral receptor function is preserved, indicating overall protein folding is intact. Site-directed mutagenesis of conserved aspartates, 32Pi uptake assay in Xenopus laevis oocytes, retroviral receptor function assay as folding control The FEBS journal High 15955065
2006 Human PiT2 (SLC20A2) exhibits positive cooperativity in Pi uptake (half-maximal activity ~163 µM Pi), can perform Na+-independent Pi transport at acidic pH (unlike PiT1), and Na+ transport by PiT2 occurs even without Pi or when Pi transport is knocked out (decoupling of Na+ from Pi transport), with putative transmembrane residues E55 and E575 responsible for linking Pi import to Na+ transport. 32Pi and 22Na+ uptake assays in Xenopus laevis oocytes expressing wild-type and transport-knockout PiT2 mutants American journal of physiology. Cell physiology High 16790504
2002 PiT2 (SLC20A2) forms homo-oligomeric assemblies at the cell surface; the conformation/abundance of these assemblies varies with extracellular inorganic phosphate concentration independently of new protein synthesis, and this structural reorganization correlates with changes in phosphate uptake and retrovirus susceptibility. Chemical cross-linking of living cells, co-immunoprecipitation of differentially tagged PiT2 molecules, detergent-resistant assembly detection, functional phosphate uptake and virus infection assays Journal of virology High 11932396
2004 Mutation of a serine residue conserved in each of the two PD001131 homology domains of PiT2 severely impairs phosphate transport but preserves retroviral receptor susceptibility; extracellular inorganic phosphate-induced conformational changes of cell-surface PiT2 oligomers still occur in these transport-incompetent mutants, indicating that structural reorganization is driven by ion binding rather than the full transport cycle. Site-directed mutagenesis of conserved serines in each PD domain, Pi uptake assay, virus infection assay, chemical cross-linking in CHO cells expressing mutant PiT2 Journal of molecular biology High 15184021
1999 Phosphate uptake and amphotropic retrovirus entry via PiT-2 (SLC20A2) are inversely regulated by extracellular phosphate concentration through posttranslational modifications of cell-surface PiT-2 molecules, not through changes in surface abundance. PiT-2 physically associates with actin, and actin network organization (stress fibers) determines cell-surface distribution, internalization of PiT-2 upon virus binding, and capacity for retrovirus entry. Phosphate uptake assay with varied extracellular Pi, retrovirus infection assay, sulfhydryl reagent inhibition, co-immunoprecipitation of PiT-2 with actin, cytochalasin D/LPA treatment to disrupt actin, confocal imaging of PiT-2 distribution Journal of virology Medium 10196273
2000 Upon productive A-MuLV infection of NIH 3T3 cells, PiT-2 (SLC20A2) is redistributed from the plasma membrane to a distinct intracellular punctate compartment (not Golgi, ER, endosomes, lysosomes, or mitochondria) that co-localizes with virus, causing superinfection interference; this redistribution is specific to A-MuLV (which binds PiT-2) and does not occur after ecotropic MuLV infection. Laser scanning confocal microscopy of epitope- and GFP-tagged PiT-2 in virus-infected NIH 3T3 cells, co-localization with organelle markers, Pi uptake assay, retrovirus infection assay Journal of virology High 10684301
1999 Activation of Pit-2 (SLC20A2) Na+-dependent phosphate uptake by phorbol ester is specifically mediated through the novel PKC isotype PKCepsilon: PMA-induced Pi uptake increase is blocked by amphotropic MuLV infection (PiT-2-specific) but not by GALV infection (PiT-1-specific); bisindolylmaleimide (pan-PKC inhibitor) blocks activation; overexpression of PKCepsilon (but not PKCα, PKCδ, PKCζ) mimics PMA; and PKCepsilon antisense oligonucleotides reduce PMA-induced uptake. Na+-dependent Pi uptake assay, retrovirus interference assay to distinguish PiT-1 vs PiT-2, PKC isotype overexpression and antisense oligonucleotide knockdown, selective pharmacological inhibitors The Journal of biological chemistry High 10066763
2011 The minimal Pi-transporting unit of human PiT2 spans its N-terminal and C-terminal transmembrane backbone; histidine H502 in the C-terminal PiT family signature sequence is critical for Pi transport; a large internal loop deletion (removing residues R254-V483) yields fully functional transport; further deletion (removing L183-V483 plus two TM domains) still supports low-level Pi transport, analogous to bacterial phosphate permeases. Truncation and deletion mutagenesis of PiT2, Pi uptake assay in Xenopus oocytes, retroviral receptor function assay as folding control BMC biochemistry High 21586110
2004 Extracellular domain 1 (ECD1) of human PiT2 (SLC20A2), as defined by the revised 12-TM topology model, is required for amphotropic murine leukemia virus (A-MuLV) binding and infection; this was demonstrated by a direct receptor-binding assay distinguishing binding from post-binding entry steps. PiT1-PiT2 chimeric receptor constructs expressed in CHO cells, A-MuLV receptor-binding assay, infection assay Journal of virology Medium 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 by chronic high-Pi diet and decreased (with slower kinetics than NaPi-IIa) upon switching from low- to high-Pi diet, suggesting a role in renal phosphate reabsorption. Western blot and immunohistochemistry of rat kidney slices and brush-border membrane fractions from rats on defined dietary Pi regimens American journal of physiology. Renal physiology Medium 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: PiT-2 knockdown in PiT-1-deleted VSMCs decreased phosphate uptake and calcification, while PiT-2 overexpression restored these parameters in PiT-1-deficient human VSMCs, demonstrating redundant roles for PiT-1 and PiT-2 in VSMC calcification. VSMC-specific PiT-1 conditional knockout mice, siRNA knockdown of PiT-2, overexpression of PiT-2, sodium-dependent phosphate uptake assay, in vitro matrix calcification assay Arteriosclerosis, thrombosis, and vascular biology High 23968976
2013 Knockout of Slc20a2 in mice is sufficient to cause brain calcifications in thalamus, basal ganglia, and cortex, demonstrating that reduced PiT2 expression alone—without any other genetic lesion—causes the neuropathological hallmark of familial idiopathic basal ganglia calcification. Slc20a2 knockout mice, histological analysis of brain calcifications Journal of molecular neuroscience : MN High 23934451
2015 Slc20a2-knockout mice have significantly elevated inorganic phosphate (Pi) concentrations in cerebrospinal fluid (CSF), indicating that PiT2 functions to export Pi from or regulate Pi levels in the CSF compartment. CSF Pi measurement by colorimetry in Slc20a2 knockout vs. wild-type mice Neurogenetics Medium 26660102
2016 Slc20a2 is expressed in choroid plexus, ependyma, and arteriolar smooth muscle cells in the mouse brain; haploinsufficient Slc20a2+/- mice develop age-dependent basal ganglia calcification in glymphatic pathway-associated arterioles with abnormally high CSF phosphate levels and hydrocephalus; siRNA knockdown of Slc20a2 in smooth muscle cells increases susceptibility to high phosphate-induced calcification in vitro. Immunohistochemistry, Slc20a2+/- mouse model, CSF Pi measurement, siRNA knockdown in smooth muscle cells, in vitro calcification assay, micro-CT Brain pathology (Zurich, Switzerland) High 26822507
2017 Pi-regulated heterodimerization of PiT1 and PiT2 (SLC20A2) underlies extracellular phosphate sensing independently of Pi uptake: deletion of either PiT1 or PiT2 blunts Pi-dependent ERK1/2 phosphorylation and downstream gene up-regulation; transport-deficient PiT mutants still rescue ERK1/2 signaling; cross-linking and BRET show PiT1-PiT2 form abundant homodimers and Pi-regulated low-abundance heterodimers; substitution of putative Pi-binding residue Ser-113 in PiT2 abolishes Pi-regulated heterodimerization. Genetic deletion (KO cells), cross-linking, bioluminescence resonance energy transfer (BRET), site-directed mutagenesis of Pi-binding residues, ERK1/2 phosphorylation assay, gene expression analysis The Journal of biological chemistry High 29233890
2018 PiT2/Slc20a2 is required for appropriate Pi-dependent secretion of FGF23 from bone: PiT2 KO mice show abnormally normal intact FGF23 serum levels on low-Pi diet and suppressed iFGF23/cFGF23 ratios irrespective of Pi load; ex vivo isolated long bone shafts from PiT2 KO mice fail to properly adjust Fgf23 secretion in response to Pi, independently of endocrine loops, identifying PiT2 as a potential endocrine Pi sensor in bone. PiT2 global KO mice fed Pi-modified diets, ex vivo isolated long bone shaft assay, adenovirus-mediated PiT1 deletion, measurement of intact and C-terminal FGF23, serum Pi, αKlotho expression Molecular metabolism High 29551636
2020 SLC20A2 and XPR1 function as a coupled phosphate uptake/efflux axis for cellular phosphate homeostasis: overexpression of WT SLC20A2 increases both Pi uptake and Pi efflux (via XPR1), while PFBC-associated SLC20A2 variants do not; SLC20A2 depletion strongly decreases XPR1-mediated Pi efflux; this SLC20A2-XPR1 cross-talk depends on inositol pyrophosphates (PP-IPs) through IP6K1/2, as IP6K inhibition abolishes XPR1-mediated efflux regulation. Overexpression and siRNA knockdown/KO of SLC20A2 and XPR1, Pi uptake and efflux assays, ATP measurement, IP6K1/2 gene inactivation and pharmacological inhibition, XPR1 PP-IP binding pocket mutant The Journal of biological chemistry High 32393577
2016 Disease-associated SLC20A2 missense variants (PiT2-D28N and PiT2-E575K) can exert dominant-negative effects on wild-type PiT2 Pi transport function in mammalian cells (Slc20a2-/- mouse cells co-expressing human WT and variant PiT2), reducing Pi uptake below haploinsufficiency levels, potentially contributing to earlier/more severe disease onset. Co-expression of WT and variant PiT2 in Slc20a2-/- mouse cells (Xenopus oocyte and mammalian cell systems), Pi uptake assay Journal of molecular neuroscience : MN Medium 27943094
2017 The loop7 intracellular domain of PiT2 (SLC20A2) is required for cell-surface trafficking of PiT2 and for neurite outgrowth in Neuro2A cells; PiT2 interacts with the light chain 1 of microtubule-associated protein 1B (MAP1B); mutations disrupting the MAP1B-binding site impair neurite outgrowth, whereas Pi transport-deficient PiT2 mutants do not, indicating a Pi transport-independent function in neuronal morphology. Co-immunoprecipitation of PiT2 with MAP1B-LC1, deletion/mutation of MAP1B binding sites, neurite outgrowth assay in Neuro2A cells, surface trafficking assay, Drosophila dPiT-Futsch interaction and NMJ analysis Scientific reports Medium 29259219
2022 PiT2-loop7 missense mutations (p.T390A and p.S434W) decrease Pi transport activity by reducing cell-surface levels of PiT2 through impaired AMPK- or AKT-mediated phosphorylation of loop7; in contrast, PD-domain missense mutations (p.S121C and p.S601W) impair Pi transport by disrupting substrate-binding without affecting PiT2 phosphorylation or surface localization. Site-directed mutagenesis, Pi transport assay, cell surface biotinylation, AMPK/AKT activity and phosphorylation analysis Neuroscience bulletin Medium 35713844
2018 PiT-2 haploinsufficiency in VSMCs leads to decreased sodium-dependent phosphate uptake, increased phosphate-induced calcification, and lower osteoprotegerin levels in vitro; osteoprotegerin supplementation attenuates calcification, indicating PiT-2 protects against vascular calcification partly through regulation of osteoprotegerin. PiT-2 heterozygous KO mice, cultured VSMCs from KO mice, sodium-dependent Pi uptake assay, matrix calcification assay, osteoprotegerin measurement and supplementation Kidney international Medium 30041812
2016 Calcitriol (vitamin D receptor agonist) selectively upregulates SLC20A2 but not SLC20A1 or XPR1 in calcifying SaOs-2 cells, and CRISPR-mediated knockdown of SLC20A2 ablates vitamin D-mediated inhibition of calcification, demonstrating that SLC20A2 is mechanistically required for calcitriol's anti-calcification effect. RT-qPCR for transporter expression, Alizarin Red calcification assay, CRISPR knockdown of SLC20A2, calcitriol treatment Scientific reports Medium 27184385
2024 In astrocytes, PiT2 (SLC20A2) is distributed over the entire astrocyte process while XPR1 is localized to end-feet on blood vessels; this polarized distribution enables directional Pi import-export capacity; astrocyte-specific knockout of Pit2 disrupts brain Pi homeostasis; PiT2-mediated Pi uptake is facilitated by the PFBC-associated galactosidase MYORG; astrocyte-specific re-expression of PiT2 in Pit2-KO mice suppresses brain calcification. Astrocyte-specific conditional KO of Pit2 and Xpr1, immunofluorescence localization, brain Pi homeostasis measurement, rescue by astrocyte-specific Pit2 re-expression, co-functional analysis with MYORG Neuron High 39019040
2024 Intronic SLC20A2 variants cause primary familial brain calcification by altering splicing machinery binding to cryptic exons, leading to aberrant pre-mRNA splicing and premature translation termination; splice-switching antisense oligonucleotides (ASOs) restore functional SLC20A2 expression in patient cells; intracerebroventricular ASO administration in humanized SLC20A2-KI mice reduces CSF Pi and suppresses brain calcification. Minigene splicing assay, RT-PCR, patient cell ASO treatment, humanized SLC20A2-KI mouse model, intracerebroventricular ASO injection, CSF Pi measurement, brain histology/imaging Neuron High 39121859
2020 Pit1 and Pit2 are both essential for normal skeletal myofiber function and survival: simultaneous conditional deletion of both transporters in skeletal muscle causes atrophy and death by P13; individual Pit2 deletion reduces running activity in a gene-dose dependent manner; loss of both transporters reduces ERK1/2 activation and stimulates AMPK, consistent with energy-stress phosphate sensing; Pi transport-dependent and ERK1/2-dependent metabolic Pi sensing pathways underlie these effects in C2C12 myoblasts. Conditional KO mice (skeletal muscle-specific, using human skeletal actin-Cre), behavioral testing (running, grip strength), ERK1/2 and AMPK phosphorylation assay, C2C12 oxygen consumption rate measurement Scientific reports High 32080237
2024 Slc20a2 (PiT-2) promotes hippocampal neuronal branching and survival independently of its phosphate transport function; Slc20a1 (PiT-1) promotes synaptic plasticity through a likely Otoferlin-dependent regulation of synaptic vesicle trafficking affecting the GABAergic system; these two transporters are differentially distributed in the hippocampus and regulate cognition by distinct mechanisms. Hippocampal conditional KO mice, electrophysiology (LTP), behavioral analyses, molecular pathway analysis, neuronal morphology assessment Cell death & disease Medium 38195526
2017 A novel SLC20A2 duplication mutation (p.Trp626_Thr629dup) does not reduce PiT-2 protein expression in patient fibroblasts but alters PiT-2 subcellular localization and reduces Pi uptake, indicating that mislocalization—not loss of expression—is the pathogenic mechanism for this variant. Patient primary fibroblast analysis, immunofluorescence for PiT-2 localization, Pi uptake assay Journal of cellular physiology Medium 28722801
2019 Several novel SLC20A2 missense mutations identified in PFBC patients impair phosphate transport when expressed in CHO cells; partial preservation of Pi transport activity (27.8% of reference) by variant c.680C>T was found in healthy family members, suggesting that partial Pi transport function may be insufficient to induce brain calcification. Stable expression of variant SLC20A2 proteins in Flp-In CHO cells, Pi transport activity assay, cell membrane localization assessment Scientific reports Medium 31754123
2019 SLC20A2 variants cause loss of Pi transport function in endothelial cells derived from patient iPSCs: patient-derived iPSC-endothelial cells show significantly decreased Pi transport activity compared to controls without altered SLC20A2 family member expression, confirming pathogenic mechanism in a disease-relevant cell type. Patient iPSC derivation, differentiation to endothelial cells, Pi transport assay, CHO cell expression of variant proteins with Flp-In system, gene expression analysis Biochemical and biophysical research communications Medium 30704756
2022 Dysfunctional PiT-2 in PFBC patient iPSC-derived neurons and astrocytes leads to imbalanced intracellular Pi, disrupted Golgi apparatus structure, impaired autophagy with increased mTOR activity, damaged mitochondria, and increased apoptosis in dopaminergic neurons and astrocytes. Patient iPSC derivation (SLC20A2 c.613G>A or del exon10), differentiation to neurons and astrocytes, Golgi structure analysis, autophagy and mTOR pathway assessment, mitochondrial analysis, apoptosis measurement Biochemical and biophysical research communications Medium 36584480
2020 Intestinal epithelial-specific deletion of Pit-2 does not affect systemic phosphate homeostasis under normal dietary conditions but leads to exacerbated hypercalciuria and sustained elevation of 1,25(OH)2 vitamin D3 in response to dietary phosphate restriction, indicating that intestinal Pit-2 plays a modulatory role in Pi homeostatic responses under low-Pi conditions. Villin-Cre driven intestinal epithelial Pit-2 conditional KO mice, dietary Pi manipulation, measurement of serum Pi, electrolytes, 1,25-vitamin D3, urine Ca, intestinal Pi transport tracers Acta physiologica (Oxford, England) Medium 32564464

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 209 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 123 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 112 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 71 29551636
2014 Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan. Neurology 71 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) 64 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
2013 SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia. Neurogenetics 60 24135862
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
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 52 26660102
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 49 26635128
2013 Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification. PloS one 49 23437308
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 46 30041812
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
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
2018 Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1). Journal of the neurological sciences 44 29627011
2013 Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification. Gene 42 23939468
2019 Spectrum of SLC20A2, PDGFRB, PDGFB, and XPR1 mutations in a large cohort of patients with primary familial brain calcification. Human mutation 41 30609140
2006 Characterization of transport mechanisms and determinants critical for Na+-dependent Pi symport of the PiT family paralogs human PiT1 and PiT2. American journal of physiology. Cell physiology 41 16790504
1999 Modulation of phosphate uptake and amphotropic murine leukemia virus entry by posttranslational modifications of PIT-2. Journal of virology 41 10196273
2012 NELL-1 increases pre-osteoblast mineralization using both phosphate transporter Pit1 and Pit2. Biochemical and biophysical research communications 38 22580275
2001 Identification of envelope determinants of feline leukemia virus subgroup B that permit infection and gene transfer to cells expressing human Pit1 or Pit2. Journal of virology 38 11435563
2014 First report of a de novo mutation at SLC20A2 in a patient with brain calcification. Journal of molecular neuroscience : MN 35 24969325
2018 Mice Knocked Out for the Primary Brain Calcification-Associated Gene Slc20a2 Show Unimpaired Prenatal Survival but Retarded Growth and Nodules in the Brain that Grow and Calcify Over Time. The American journal of pathology 33 29803831
2001 Feline Pit2 functions as a receptor for subgroup B feline leukemia viruses. Journal of virology 33 11602698
2004 Transport-deficient Pit2 phosphate transporters still modify cell surface oligomers structure in response to inorganic phosphate. Journal of molecular biology 31 15184021
2016 Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and lamininα1 expressing cells. Reproductive biology 30 26952749
2005 Evolutionary and experimental analyses of inorganic phosphate transporter PiT family reveals two related signature sequences harboring highly conserved aspartic acids critical for sodium-dependent phosphate transport function of human PiT2. The FEBS journal 29 15955065
2002 Pit2 assemblies at the cell surface are modulated by extracellular inorganic phosphate concentration. Journal of virology 29 11932396
2000 Subcellular redistribution of Pit-2 P(i) transporter/amphotropic leukemia virus (A-MuLV) receptor in A-MuLV-infected NIH 3T3 fibroblasts: involvement in superinfection interference. Journal of virology 28 10684301
2016 Vitamin-D receptor agonist calcitriol reduces calcification in vitro through selective upregulation of SLC20A2 but not SLC20A1 or XPR1. Scientific reports 27 27184385
2015 Generalized epilepsy in a family with basal ganglia calcifications and mutations in SLC20A2 and CHRNB2. European journal of medical genetics 25 26475232
1999 Up-regulation of the Pit-2 phosphate transporter/retrovirus receptor by protein kinase C epsilon. The Journal of biological chemistry 25 10066763
1996 The Japanese feral mouse Pit1 and Pit2 homologs lack an acidic residue at position 550 but still function as gibbon ape leukemia virus receptors: implications for virus binding motif. Journal of virology 23 8794342
2016 Identification of partial SLC20A2 deletions in primary brain calcification using whole-exome sequencing. European journal of human genetics : EJHG 22 27245298
2016 Primary Brain Calcification Causal PiT2 Transport-Knockout Variants can Exert Dominant Negative Effects on Wild-Type PiT2 Transport Function in Mammalian Cells. Journal of molecular neuroscience : MN 22 27943094
2024 Antisense oligonucleotides enhance SLC20A2 expression and suppress brain calcification in a humanized mouse model. Neuron 21 39121859
2020 Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival. Scientific reports 21 32080237
2004 Identification of an extracellular domain within the human PiT2 receptor that is required for amphotropic murine leukemia virus binding. Journal of virology 20 14694091
2020 Intestinal epithelial ablation of Pit-2/Slc20a2 in mice leads to sustained elevation of vitamin D3 upon dietary restriction of phosphate. Acta physiologica (Oxford, England) 19 32564464
2024 Astrocytes modulate brain phosphate homeostasis via polarized distribution of phosphate uptake transporter PiT2 and exporter XPR1. Neuron 18 39019040
2021 Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2. European journal of human genetics : EJHG 18 34267336
2017 PiT2 regulates neuronal outgrowth through interaction with microtubule-associated protein 1B. Scientific reports 18 29259219
2016 Primary familial brain calcification in the 'IBGC2' kindred: All linkage roads lead to SLC20A2. Movement disorders : official journal of the Movement Disorder Society 18 27671522
2017 Primary familial brain calcification with a novel SLC20A2 mutation: Analysis of PiT-2 expression and localization. Journal of cellular physiology 17 28722801
2015 A new SLC20A2 mutation identified in southern Italy family with primary familial brain calcification. Gene 17 25958344
2019 Identification of SLC20A2 deletions in patients with primary familial brain calcification. Clinical genetics 16 30891739
2017 Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice. Biochemical and biophysical research communications 16 29133259
2000 Effect of changes in expression of the amphotropic retroviral receptor PiT-2 on transduction efficiency and viral titer: implications for gene therapy. Human gene therapy 16 10724037
1998 Entry of amphotropic murine leukemia virus is influenced by residues in the putative second extracellular domain of its receptor, Pit2. Journal of virology 16 9573264
1995 Enhancement of retrovirus-mediated gene transduction efficiency by transient overexpression of the amphotropic receptor, GLVR-2. Nucleic acids research 16 7596842
2018 Effect of variations in dietary Pi intake on intestinal Pi transporters (NaPi-IIb, PiT-1, and PiT-2) and phosphate-regulating factors (PTH, FGF-23, and MEPE). Pflugers Archiv : European journal of physiology 15 29372301
2014 Fahr's disease linked to a novel SLC20A2 gene mutation manifesting with dynamic aphasia. Neuro-degenerative diseases 15 25348593
2020 Haploinsufficiency of the Primary Familial Brain Calcification Gene SLC20A2 Mediated by Disruption of a Regulatory Element. Movement disorders : official journal of the Movement Disorder Society 13 32506582
2019 SLC20A2 variants cause dysfunctional phosphate transport activity in endothelial cells induced from Idiopathic Basal Ganglia Calcification patients-derived iPSCs. Biochemical and biophysical research communications 13 30704756
2004 The central half of Pit2 is not required for its function as a retroviral receptor. Journal of virology 13 15308749
2000 A 13-amino-acid Pit1-specific loop 4 sequence confers feline leukemia virus subgroup B receptor function upon Pit2. Journal of virology 13 10684313
2024 Slc20a1 and Slc20a2 regulate neuronal plasticity and cognition independently of their phosphate transport ability. Cell death & disease 12 38195526
2019 Intracranial calcifications and dystonia associated with a novel deletion of chromosome 8p11.2 encompassing SLC20A2 and THAP1. BMJ case reports 11 31133547
2018 A Novel SLC20A2 Mutation Associated with Familial Idiopathic Basal Ganglia Calcification and Analysis of the Genotype-Phenotype Association in Chinese Patients. Chinese medical journal 11 29578123
2023 The phage-encoded protein PIT2 impacts Pseudomonas aeruginosa quorum sensing by direct interaction with LasR. iScience 10 37736037
2016 Primary familial brain calcification linked to deletion of 5' noncoding region of SLC20A2. Acta neurologica Scandinavica 10 27726124
1998 Lack of functional Pit-1 and Pit-2 expression on hematopoietic stem cell lines. Acta haematologica 10 9587396
2021 Severe brain calcification and migraine headache caused by SLC20A2 and PDGFRB heterozygous mutations in a five-year-old Chinese girl. Molecular genetics & genomic medicine 9 33793087
2022 SLC20A2-Associated Idiopathic basal ganglia calcification (Fahr disease): a case family report. BMC neurology 8 36397039
2019 Partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of idiopathic basal ganglia calcification. Scientific reports 8 31754123
2024 An NLR paralog Pit2 generated from tandem duplication of Pit1 fine-tunes Pit1 localization and function. Nature communications 7 38816417
2023 PSEN1/SLC20A2 double mutation causes early-onset Alzheimer's disease and primary familial brain calcification co-morbidity. Neurogenetics 7 37341843
2022 Golgi damage caused by dysfunction of PiT-2 in primary familial brain calcification. Biochemical and biophysical research communications 7 36584480
2022 Familial idiopathic basal ganglia calcification with a heterozygous missense variant (c.902C>T/p.P307L) in SLC20A2 showing widespread cerebrovascular lesions. Neuropathology : official journal of the Japanese Society of Neuropathology 6 35026865
2022 Homozygous SLC20A2 mutations cause congenital CMV infection-like phenotype. Acta neurologica Belgica 6 35881308
2021 Case Report: Two Novel Frameshift Mutations in SLC20A2 and One Novel Splice Donor Mutation in PDGFB Associated With Primary Familial Brain Calcification. Frontiers in genetics 6 34025715
2020 Cortical myoclonus and epilepsy in a family with a new SLC20A2 mutation. Journal of neurology 6 32274582
2020 A mutation in SLC20A2 (c.C1849T) promotes proliferation while inhibiting hypertrophic differentiation in ATDC5 chondrocytes. Bone & joint research 6 33135420
2020 SLC20A2-Associated Idiopathic Basal Ganglia Calcification-Related Recurrent Psychosis Response to Low-Dose Antipsychotics: A Case Report and Literature Review. Cureus 6 33532164
2019 Lack of Major Ophthalmic Findings in Patients with Primary Familial Brain Calcification Linked to SLC20A2 and PDGFB. Journal of molecular neuroscience : MN 6 30607898
2019 Generation of induced pluripotent stem cell line (ZZUi0012-A) from a patient with Fahr's disease caused by a novel mutation in SLC20A2 gene. Stem cell research 6 30776674
2018 Anticipation in a family with primary familial brain calcification caused by an SLC20A2 variant. Neurologia i neurochirurgia polska 6 29680161
2017 Induced pluripotent stem cells derived from a patient with familial idiopathic basal ganglia calcification (IBGC) caused by a mutation in SLC20A2 gene. Stem cell research 6 29034894
2006 Expression of Pit2 sodium-phosphate cotransporter during murine odontogenesis is developmentally regulated. European journal of oral sciences 6 17184235
2005 Expression of the rat renal PiT-2 phosphate transporter. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 6 15971147
2001 Molecular cloning of a murine type III sodium-dependent phosphate cotransporter (Pit-2) gene promoter. Biochimica et biophysica acta 6 11718898
2023 T-cell infiltration in the central nervous system and their association with brain calcification in Slc20a2-deficient mice. Frontiers in molecular neuroscience 5 36741925
2022 SLC20A2-related primary familial brain calcification with purely acute psychiatric symptoms: a case report. BMC neurology 5 35850697
2019 A splice site mutation causing exon 6 skipping in SLC20A2 gene in a primary familial brain calcification family. Brain research bulletin 5 30634018
2019 A likely pathogenic variant in the SLC20A2 gene presenting with progressive myoclonus. Annals of clinical and translational neurology 5 30911583
2017 Primary familial brain calcifications linked with a novel SLC20A2 gene mutation in a Chinese family. Journal of neurogenetics 5 28609135
2002 Expression of PiT1 and PiT2 retroviral receptors and transduction efficiency of tumor cells. Acta biochimica Polonica 5 12362974
1993 Pit-1 and Pit-2 role in growth hormone gene regulation. The Journal of pediatric endocrinology 5 7920986
2022 Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis. Neuroscience bulletin 4 35713844
2009 Unconventional integration of the bla gene from plasmid pIT2 during ISlacZ/hah transposon mutagenesis in Pseudomonas aeruginosa PAO1. Current microbiology 4 19189184

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