Affinage

SLC6A8

Sodium- and chloride-dependent creatine transporter 1 · UniProt P48029

Length
635 aa
Mass
70.5 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC6A8 is a Na+- and Cl--coupled, electrogenic plasma-membrane creatine transporter that supplies creatine to high-energy-demand tissues such as brain and muscle, and its loss causes X-linked cerebral creatine deficiency syndrome (PMID:11326334, PMID:9882430). Transport follows a stoichiometry of at least two Na+ and one Cl- per creatine with a Km near 20 µM, and the carrier's electrogenic current and creatine uptake are inseparable functions (PMID:9882430, PMID:22644605). Beyond creatine, SLC6A8 imports guanidinoacetate—shuttling this precursor between the rare brain cells that express creatine-synthesis enzymes (AGAT, GAMT) so that creatine can be made despite intact synthetic machinery—as well as cyclocreatine (PMID:19879361, PMID:32124083). The transporter's maximal turnover rate is tuned by a network of kinases without changes in substrate affinity: SGK1/SGK3 acting through mTOR and PIKfyve increase activity, Klotho stabilizes the carrier at the membrane, while JAK2, JAK3, SPAK/OSR1, and GSK3β suppress it (PMID:16036218, PMID:16466692, PMID:17982255, PMID:25531216, PMID:22407360, PMID:26666525, PMID:25531585, PMID:27978525). Pathogenic variants act through two broad mechanisms—ER retention and trafficking failure or disruption of the substrate-binding pocket/transport machinery while membrane localization is preserved—and small-molecule proteostasis correctors can restore surface trafficking and creatine uptake of mutant transporter in cells and in vivo (PMID:32207963, PMID:38070861, PMID:38233148, PMID:39418577). In immune cells, SLC6A8-mediated creatine import reprograms macrophage polarization by suppressing IFN-γ–JAK–STAT1 signaling and supporting IL-4–STAT6–arginase 1 chromatin remodeling (PMID:31399282). In cancer, transcriptional induction of SLC6A8 supports tumor cell survival, and pharmacological inhibition depletes phosphocreatine/ATP, activates ERK2 to drive ferroptosis, and suppresses tumor growth (PMID:33990217, PMID:34613776, PMID:40892544). Genetic ablation in mice recapitulates the human phenotype, producing cerebral creatine deficiency with learning/memory deficits and hyperactivity, and skeletal muscle atrophy with mitochondrial dysfunction (PMID:21249153, PMID:29384270, PMID:31520365, PMID:39952955).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established the fundamental transport mechanism of SLC6A8, defining it as an ion-coupled creatine carrier and fixing its kinetics and ion stoichiometry.

    Evidence Heterologous expression in Xenopus oocytes with electrophysiology, ion-substitution kinetics, and site-directed mutagenesis

    PMID:9882430

    Open questions at the time
    • No structural basis for ion/substrate coupling resolved
    • Physiological tissue context not addressed in oocytes
  2. 2001 High

    Linked SLC6A8 loss of function directly to human disease, identifying it as the X-linked creatine transporter responsible for cerebral creatine deficiency syndrome.

    Evidence Creatine uptake assay in patient fibroblasts with a hemizygous nonsense mutation plus brain proton MRS

    PMID:11326334

    Open questions at the time
    • Did not establish whether deficit is cell-autonomous or systemic
    • Mechanism linking creatine loss to neurological phenotype unresolved
  3. 2006 Medium

    Confirmed that the creatine uptake defect in patient cells is solely attributable to SLC6A8 by genetic rescue.

    Evidence Transient transfection of wild-type SLC6A8 cDNA into deficient fibroblasts with radiolabeled creatine uptake

    PMID:16763899

    Open questions at the time
    • Single rescue endpoint
    • Does not address in vivo neuronal context
  4. 2009 Medium

    Explained why SLC6A8 deficiency causes brain creatine deficiency despite intact synthesis enzymes, by showing the transporter shuttles guanidinoacetate between AGAT- and GAMT-expressing cells.

    Evidence Cell-by-cell co-expression analysis in rat CNS and reaggregating brain cell uptake/competition assays

    PMID:19879361

    Open questions at the time
    • Direct demonstration that SLC6A8 (not another carrier) mediates the guanidinoacetate flux in vivo incomplete
    • Quantitative contribution to total brain creatine unknown
  5. 2005 Medium

    Opened the regulatory dimension of SLC6A8 by showing kinases set its maximal transport rate without affecting affinity, identifying SGK1/SGK3 as positive regulators.

    Evidence Xenopus oocyte co-expression with wild-type, constitutively active, and kinase-dead SGK isoforms; voltage clamp

    PMID:16036218

    Open questions at the time
    • Direct phosphorylation of SLC6A8 not demonstrated
    • Single expression system
  6. 2007 Medium

    Defined the SGK1 regulatory cascade upstream and downstream, placing mTOR above SGK1 and PIKfyve below it.

    Evidence Xenopus oocyte co-expression with rapamycin, kinase-dead SGK1, and PIKfyve S318A mutants; voltage clamp

    PMID:16466692 PMID:17982255

    Open questions at the time
    • Molecular target of phosphorylation on the trafficking machinery unidentified
    • Single lab/oocyte system
  7. 2014 Medium

    Expanded the negative-regulatory network (JAK2, SPAK/OSR1) and identified Klotho as a membrane-stabilizing positive regulator, distinguishing insertion/removal effects.

    Evidence Xenopus oocyte voltage clamp with kinase-dead controls, brefeldin A insertion/removal assays, recombinant Klotho and β-glucuronidase inhibitor

    PMID:22407360 PMID:25531216 PMID:25531585

    Open questions at the time
    • Whether regulation occurs in mammalian neurons/muscle in vivo untested
    • Direct biochemical interactions not shown
  8. 2016 Medium

    Completed the kinase regulatory map with JAK3 and GSK3β as suppressors, including epistasis with PKB/Akt and pharmacological reversal.

    Evidence Xenopus oocyte co-expression with active/inactive kinase mutants, WHI-P154, lithium, and PKB/Akt co-expression

    PMID:26666525 PMID:27978525

    Open questions at the time
    • Physiological stimuli engaging these kinases on SLC6A8 unknown
    • No in vivo validation
  9. 2012 High

    Resolved how non-truncating disease variants disable the transporter, showing loss of both electrogenic and uptake activity despite correct membrane targeting.

    Evidence Xenopus oocyte voltage clamp, [14C]-creatine uptake, and immunolocalization of variants; complementary fibroblast variant panel

    PMID:17465020 PMID:22644605

    Open questions at the time
    • Atomic-level mechanism of variant-induced transport failure not resolved
    • Limited to a defined variant set
  10. 2011 High

    Established a whole-animal model demonstrating SLC6A8 is required for brain and muscle creatine and for normal cognition.

    Evidence Germline Slc6a8 knockout mice with HPLC neurochemistry and behavioral testing

    PMID:21249153

    Open questions at the time
    • Could not separate brain-intrinsic from peripheral contributions
    • Cell types responsible for cognitive deficit undefined
  11. 2018 High

    Pinpointed cerebral creatine loss, rather than peripheral deficiency, as the cause of cognitive deficits, and later localized hyperactivity to dopaminergic neurons.

    Evidence Nestin-cre and DAT-cre conditional Slc6a8 knockout mice with MRS, neurochemistry, and behavioral phenotyping

    PMID:29384270 PMID:31520365

    Open questions at the time
    • Molecular link from neuronal creatine to behavior unresolved
    • Other neuronal subtypes not dissected
  12. 2019 High

    Revealed a non-energetic immunometabolic role: creatine imported via SLC6A8 reprograms macrophage polarization by reciprocally modulating STAT1 and STAT6 pathways.

    Evidence Macrophage-specific Slc6a8 knockout with multi-omics, cytokine stimulation, chromatin remodeling assays, and in vivo infection models

    PMID:31399282

    Open questions at the time
    • Direct molecular targets of intracellular creatine in these pathways not fully defined
    • Relevance to human inflammatory disease untested here
  13. 2021 High

    Identified SLC6A8 as a therapeutic target in cancer, where its inhibition depletes phosphocreatine/ATP and suppresses tumor growth, and where its NF-κB-driven induction supports tumor survival.

    Evidence Small-molecule inhibitor RGX-202 in tumor models with pharmacodynamics in mice and patients; SLC6A8 knockdown/overexpression in TNBC with metabolic and xenograft assays

    PMID:33990217 PMID:34613776

    Open questions at the time
    • Patient efficacy endpoint not established
    • Tumor-type dependence of dependency incompletely mapped
  14. 2023 Medium

    Mapped a transcriptional control circuit (CARD9-BCL10-MALT1 → p65/NF-κB) governing SLC6A8 expression and creatine import in dendritic cells.

    Evidence CARD9 knockout mice, DC co-culture, metabolomics, p65 ChIP/promoter binding, and adoptive transfer

    PMID:37089447

    Open questions at the time
    • Generality of this regulatory axis beyond DCs unknown
    • Single lab
  15. 2023 High

    Defined the proteostatic basis of disease variants, showing pathogenic mutations cause ER retention via altered interaction interfaces, and that proteostasis modulators differentially affect wild-type and mutant transporter.

    Evidence Quantitative trafficking/expression profiling of pathogenic variants, mass-spectrometry interactomics, and conformer structural modeling in HEK293(T)

    PMID:32207963 PMID:38070861

    Open questions at the time
    • Specific ER quality-control machinery retaining variants not fully identified
    • Experimental structure absent (modeling only)
  16. 2024 High

    Demonstrated pharmacological rescue of disease alleles, with small-molecule correctors restoring mutant SLC6A8 trafficking and uptake in cells and raising brain creatine in a knock-in mouse.

    Evidence Chemoproteomic ligand discovery, trafficking/uptake assays in CRISPR knock-in cells, and an oral corrector in Slc6a8P544L knock-in mice

    PMID:39418577

    Open questions at the time
    • Breadth of variants rescuable not established
    • Therapeutic efficacy on behavioral phenotypes untested
  17. 2025 Medium

    Uncovered a creatine-ERK2-FSP1 signaling axis explaining how SLC6A8 inhibition triggers ferroptosis, and tied SLC6A8 loss to muscle atrophy via mitochondrial calcium and IGF1-Akt signaling.

    Evidence Creatine-ERK2 binding and FSP1 Thr109 phosphorylation mapping with RGX-202 and xenografts; Slc6a8 knockout muscle with mitochondrial Ca2+/ATP assays and ubiquitin-ligase/Akt profiling

    PMID:39952955 PMID:40892544

    Open questions at the time
    • Direct structural basis of creatine-ERK2 binding not resolved
    • Causal hierarchy between mitochondrial Ca2+ and atrophy pathways incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse signaling and metabolic roles of imported creatine—kinase regulation of the carrier, immunometabolic reprogramming, and oncogenic ERK2/FSP1 control—are integrated at the molecular level, and whether corrector therapy reverses neurological phenotypes, remains open.
  • No experimental structure of human SLC6A8 in the corpus
  • Direct phosphosite on the transporter for any regulatory kinase unidentified
  • Behavioral rescue by correctors not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3 R-HSA-168256 Immune System 2
Partners
ERK2KLOTHO

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SLC6A8 encodes a Na+- and Cl--dependent creatine transporter; loss-of-function mutations cause absent creatine uptake in fibroblasts, establishing SLC6A8 as the X-linked creatine transporter responsible for cerebral creatine deficiency syndrome. Creatine uptake assay in patient fibroblasts with hemizygous nonsense mutation; proton MRS of brain American journal of human genetics High 11326334
1999 Human SLC6A8 (CRT-1) expressed in Xenopus oocytes mediates Na+- and Cl--dependent creatine uptake with Km ~20 µM; stoichiometry requires at least two Na+ ions and one Cl- per creatine molecule; transport is inhibited by protein kinase C activator PMA but not by PKA activator 8-bromo-cAMP. Heterologous expression in Xenopus oocytes, electrophysiology, ion-substitution kinetics, pharmacology, site-directed mutagenesis (A285P variant) Archives of biochemistry and biophysics High 9882430
2005 The serum- and glucocorticoid-inducible kinases SGK1 and SGK3 (but not SGK2 or PKB) positively regulate SLC6A8 transport activity by increasing its maximal transport rate without altering substrate affinity. Heterologous expression in Xenopus oocytes with co-expression of wild-type, constitutively active, and kinase-dead SGK isoforms; dual-electrode voltage clamp Biochemical and biophysical research communications Medium 16036218
2006 mTOR stimulates SLC6A8 creatine transport activity (maximal rate), an effect blocked by rapamycin and by co-expression of kinase-dead SGK1, placing mTOR upstream of SGK1 in SLC6A8 regulation. Xenopus oocyte co-expression, dual-electrode voltage clamp, rapamycin inhibition Biochemical and biophysical research communications Medium 16466692
2007 PIKfyve, acting downstream of SGK1 phosphorylation at its SGK consensus site (S318), mediates SGK1-dependent stimulation of SLC6A8 transport activity; the inactive SGK1 mutant K127N blocks the PIKfyve effect, and S318A-PIKfyve blocks SGK1's effect on SLC6A8. Xenopus oocyte co-expression of SLC6A8, PIKfyve, and SGK1 variants; dual-electrode voltage clamp Cellular physiology and biochemistry Medium 17982255
2012 JAK2 down-regulates SLC6A8 creatine transport by decreasing maximal transport rate without affecting substrate affinity; kinase-dead JAK2 (K882E) has no effect; JAK2 does not alter the rate of carrier removal from the membrane (brefeldin A experiment), suggesting interference with carrier insertion. Xenopus oocyte co-expression, dual-electrode voltage clamp, brefeldin A experiment, JAK2 inhibitor AG490 The Journal of membrane biology Medium 22407360
2014 SPAK (constitutively active T233E-SPAK, WNK-insensitive T233A-SPAK, but not catalytically inactive D212A-SPAK) and OSR1 (wild-type, T185E, T185A, but not D164A-OSR1) negatively regulate SLC6A8 by decreasing maximal transport rate. Xenopus oocyte co-expression of SLC6A8 with SPAK/OSR1 variants; dual-electrode voltage clamp Kidney & blood pressure research Medium 25531585
2014 Klotho protein upregulates SLC6A8 creatine transport activity by stabilizing the carrier at the cell membrane; this effect requires β-glucuronidase activity of Klotho and is reproduced by recombinant soluble Klotho; Klotho delays brefeldin A-induced decline of creatine-induced current. Xenopus oocyte co-expression, dual-electrode voltage clamp, brefeldin A membrane-insertion block, β-glucuronidase inhibitor DSAL, recombinant Klotho protein Kidney & blood pressure research Medium 25531216
2015 JAK3 negatively regulates SLC6A8 creatine transport, decreasing maximal transport rate; constitutively active A568V-JAK3 mimics this effect while inactive K851A-JAK3 does not; the JAK3 inhibitor WHI-P154 reverses the suppression. Xenopus oocyte co-expression, dual-electrode voltage clamp, pharmacological inhibitor Neuro-Signals Medium 26666525
2016 GSK3β down-regulates SLC6A8 creatine transport (maximal transport rate); this effect is blocked by co-expression of PKB/Akt and reversed by lithium treatment; catalytically inactive K85R-GSK3β has no effect. Xenopus oocyte co-expression, dual-electrode voltage clamp, lithium treatment Cellular physiology and biochemistry Medium 27978525
2007 Functional assay using site-directed mutagenesis and transient transfection of SLC6A8-deficient fibroblasts demonstrated that nine missense/deletion variants are pathogenic (abolish creatine uptake) while four variants are non-pathogenic, establishing structure-function relationships for the transporter. Site-directed mutagenesis, transient transfection into SLC6A8-deficient fibroblasts, radiolabeled creatine uptake assay Human mutation High 17465020
2012 Four non-truncating SLC6A8 mutations cause complete loss of both electrogenic (current) and creatine transport activity despite proper targeting of mutant protein to the plasma membrane; the electrogenic and transport activities of SLC6A8 could not be dissociated by any tested creatine analog. Xenopus oocyte expression, dual-electrode voltage clamp, [14C]-creatine uptake, immunofluorescence and western blot for subcellular localization Journal of inherited metabolic disease High 22644605
2006 Overexpression of wild-type SLC6A8 ORF in SLC6A8-deficient fibroblasts fully restores creatine uptake, proving that loss of SLC6A8 function is solely responsible for the creatine uptake defect in patient cells. Transient transfection of wild-type SLC6A8 cDNA into deficient primary fibroblasts, radiolabeled creatine uptake assay Journal of inherited metabolic disease Medium 16763899
2009 In rat CNS, cells co-expressing both AGAT and GAMT (capable of autonomous creatine synthesis) are rare (<20% in most structures); brain cells take up guanidinoacetate and convert it to creatine, and this uptake is competed by creatine, indicating that SLC6A8 transports guanidinoacetate between AGAT- and GAMT-expressing cells to enable creatine synthesis—explaining why SLC6A8 deficiency causes creatine deficiency despite intact synthesis enzymes. Cell-by-cell co-expression analysis by in situ hybridization/immunohistochemistry in rat CNS; reaggregating brain cell cultures with radiolabeled guanidinoacetate uptake and competition assay Neurobiology of disease Medium 19879361
2011 Ubiquitous Slc6a8 knockout (CrT−/y) mice lack creatine in brain and muscle, develop learning and memory deficits (Morris water maze, novel object recognition, fear conditioning), and show increased serotonin and 5-HIAA in hippocampus and prefrontal cortex, establishing the mouse model of CrT deficiency. Cre/loxP knockout (exons 2–4 deletion), HPLC for creatine/neurotransmitter levels, behavioral testing PloS one High 21249153
2018 Brain-specific Slc6a8 knockout mice (Nestin-cre) have reduced cerebral creatine and increased guanidinoacetate in brain, with learning and memory deficits (Morris water maze, novel object recognition, fear conditioning) and hyperactivity, demonstrating that loss of cerebral creatine—not peripheral creatine deficiency—is responsible for cognitive deficits. Conditional KO (Nestin-cre × Slc6a8flox), MRS, behavioral testing, neurochemical assay Genes, brain, and behavior High 29384270
2019 Deletion of Slc6a8 specifically in dopaminergic (DAT-expressing) neurons causes hyperactivity throughout aging without impairing motor function, indicating creatine in dopaminergic neurons specifically modulates locomotor activity. Conditional KO (DATIREScre × Slc6a8flox), longitudinal locomotor activity and motor testing Journal of molecular neuroscience Medium 31520365
2019 Slc6a8 ablation in macrophages (genetic knockout) suppresses intracellular creatine accumulation; creatine suppresses IFN-γ–JAK–STAT1 signaling (reducing iNOS induction) and promotes IL-4–STAT6–arginase 1 expression through chromatin remodeling, thereby reprogramming macrophage polarization from M1-like to M2-like. Genetic knockout of Slc6a8 in macrophages, genomics/metabolomics/immunological assays, cytokine stimulation with IFN-γ and IL-4, STAT1/STAT6 pathway analysis, chromatin remodeling assays, in vivo infection models Immunity High 31399282
2020 Pathogenic SLC6A8 variants cause a spectrum of molecular defects including proteostatic deficiencies (reduced expression/trafficking) and disruption of the substrate-binding pocket; most variants show measurable trafficking defects; the proteostasis regulator 4-PBA enhances WT SLC6A8 activity in HEK293T cells but does not rescue the tested pathogenic variants (except minimally G132V which is temperature-sensitive). Quantitative profiling of cellular processing, trafficking, expression, and function of 8 pathogenic variants in HEK293T cells; structural modeling; 4-PBA and temperature rescue experiments Biochemistry High 32207963
2021 The small-molecule SLC6A8 inhibitor RGX-202 blocks creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP, induces tumor apoptosis, and suppresses colorectal cancer growth; antitumor efficacy correlates with tumoral creatine kinase B expression; RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial. In vitro transport inhibition assay, xenograft/syngeneic/PDX tumor models, pharmacodynamic creatine metabolite measurements in mice and human trial Science advances High 34613776
2020 Cyclocreatine is a substrate of SLC6A8; CRT is the predominant mediator of cyclocreatine uptake in HEK293 cells and in a human blood-brain barrier model (hCMEC/D3), shown by siRNA knockdown and inhibitor studies; cyclocreatine uptake is largely absent in fibroblasts from CRT-deficient patients. [14C]cyclocreatine uptake assay, siRNA knockdown of SLC6A8, pharmacological inhibition, patient fibroblasts Pharmaceutical research Medium 32124083
2023 Mass spectrometry identified protein interaction partners of wild-type SLC6A8 in HEK293 cells; pathogenic variants led to enrichment of ER protein partners, indicating that pathogenic mutations cause ER retention; structural models of inward- and outward-facing conformations showed how two variants disrupt the interaction interface of SLC6A8 with binding partners. Mass-spectrometry interactomics, homology modeling of transporter conformers, subcellular localization by imaging in HEK293 cells Journal of molecular biology Medium 38070861
2023 CARD9 deficiency reduces SLC6A8 transcription in dendritic cells by blocking p65/NF-κB activation via abolition of the CARD9-BCL10-MALT1 complex formation, preventing p65 binding to the SLC6A8 promoter, thereby decreasing creatine import into DCs and impairing DC maturation. CARD9 knockout mice, DC co-culture assays, metabolomics, ChIP/promoter binding assay for p65, CARD9-BCL10-MALT1 complex analysis, adoptive DC transfer Oncoimmunology Medium 37089447
2021 NF-κB/p65 transcriptionally upregulates SLC6A8 in hypoxic triple-negative breast cancer cells, leading to increased intracellular creatine accumulation that reduces mitochondrial ROS and activates AKT-ERK signaling to promote cell survival. SLC6A8 KD/OE in TNBC cells, promoter analysis, ROS measurements, mitochondrial respiration assays, xenograft model Journal of experimental & clinical cancer research Medium 33990217
2024 Small-molecule correctors identified by chemoproteomic affinity profiling bind SLC6A8 in cells, promote trafficking of mutant SLC6A8 variants to the cell surface, and rescue creatine uptake; in vivo, an orally bioavailable corrector increased brain creatine in heterozygous female Slc6a8P544L knock-in mice. Reactive affinity probe chemoproteomic ligand discovery, medicinal chemistry, trafficking assays, creatine uptake assays, CRISPR knock-in cell lines, knock-in mouse model, brain creatine measurement ACS chemical biology High 39418577
2025 Creatine binds ERK2 and impairs its activation by MEK1; SLC6A8 inhibition reduces creatine uptake and activates ERK2, which then phosphorylates ferroptosis suppressor protein FSP1 at Thr109 to stabilize it and inhibit ferroptosis in colorectal cancer cells. Untargeted metabolomics, creatine-ERK2 binding assay, phosphoproteomic/mutagenesis analysis of FSP1 Thr109 phosphorylation, SLC6A8 inhibition (RGX-202), xenograft models, CD8+ T cell infiltration analysis Cell reports Medium 40892544
2025 SLC6A8 knockout (CrT−/y) mice exhibit severe skeletal muscle atrophy with ultrastructural abnormalities, reduced fiber cross-sectional area, and impaired mitochondrial Ca2+ uptake, membrane potential, and ATP production; atrophy is mechanistically linked to upregulation of E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway regulated by mitochondrial Ca2+ levels. Whole-body Slc6a8 KO mice, electron microscopy, mitochondrial Ca2+ uptake assay, membrane potential measurement, ATP assay, ubiquitin ligase/Akt pathway western blotting Cell death & disease Medium 39952955
2024 The c.1699T>C (p.S567P) SLC6A8 mutation reduces maximal creatine uptake rate without altering Km or membrane localization, and structural modeling indicates the S567P substitution disrupts an interaction between S567 and Y143 residues within the transporter, impairing transport function without causing mislocalization. Xenopus oocyte expression, creatine uptake kinetics, immunofluorescence, AlphaFold structural modeling Biological & pharmaceutical bulletin Medium 38233148

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor. Cell 435 9741624
2001 X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. American journal of human genetics 305 11326334
2019 Slc6a8-Mediated Creatine Uptake and Accumulation Reprogram Macrophage Polarization via Regulating Cytokine Responses. Immunity 187 31399282
2004 High prevalence of SLC6A8 deficiency in X-linked mental retardation. American journal of human genetics 162 15154114
2006 X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Human genetics 106 16738945
2011 Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency. PloS one 96 21249153
2002 X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28. American journal of human genetics 87 11898126
2008 AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. Journal of inherited metabolic disease 80 18392746
2009 Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiology of disease 77 19879361
1999 Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Archives of biochemistry and biophysics 75 9882430
2002 X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. Annals of neurology 71 12210795
2021 Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels. Science advances 67 34613776
2008 Cloning of the cytochrome p450 reductase (crtR) gene and its involvement in the astaxanthin biosynthesis of Xanthophyllomyces dendrorhous. BMC microbiology 67 18837978
2014 Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Molecular genetics and metabolism 56 24953403
2010 Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Molecular genetics and metabolism 55 20846889
2006 Ccr4 contributes to tolerance of replication stress through control of CRT1 mRNA poly(A) tail length. Journal of cell science 53 17158920
2007 Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. Human mutation 52 17465020
2005 Two novel mutations in SLC6A8 cause creatine transporter defect and distinctive X-linked mental retardation in two unrelated Dutch families. American journal of medical genetics. Part A 51 15690373
2007 PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 49 17982255
2021 Tumour-derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8-mediated creatine import in NPM1-mutated acute myeloid leukaemia. Journal of extracellular vesicles 46 34807526
2010 CRT-1/calreticulin and the E3 ligase EEL-1/HUWE1 control hemidesmosome maturation in C. elegans development. Current biology : CB 46 20153198
2005 Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3. Biochemical and biophysical research communications 46 16036218
2004 Identification of new genes regulated by the Crt1 transcription factor, an effector of the DNA damage checkpoint pathway in Saccharomyces cerevisiae. The Journal of biological chemistry 44 15494396
2014 Upregulation of the creatine transporter Slc6A8 by Klotho. Kidney & blood pressure research 43 25531216
2000 CRTR-1, a developmentally regulated transcriptional repressor related to the CP2 family of transcription factors. The Journal of biological chemistry 41 11073954
2012 CRT1 is a nuclear-translocated MORC endonuclease that participates in multiple levels of plant immunity. Nature communications 40 23250427
2010 The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation. Journal of inherited metabolic disease 37 24137762
2007 Severe epilepsy in X-linked creatine transporter defect (CRTR-D). Epilepsia 37 17553121
2008 Characterization of cyanobacterial carotenoid ketolase CrtW and hydroxylase CrtR by complementation analysis in Escherichia coli. Plant & cell physiology 35 18987067
2020 Studies on sugar transporter CRT1 reveal new characteristics that are critical for cellulase induction in Trichoderma reesei. Biotechnology for biofuels 34 32944074
2021 SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress. Journal of experimental & clinical cancer research : CR 33 33990217
2012 Contiguous deletion of SLC6A8 and BAP31 in a patient with severe dystonia and sensorineural deafness. Molecular genetics and metabolism 33 22472424
2006 Stimulation of the creatine transporter SLC6A8 by the protein kinase mTOR. Biochemical and biophysical research communications 32 16466692
2005 Molecular genetic analysis of the yeast repressor Rfx1/Crt1 reveals a novel two-step regulatory mechanism. Molecular and cellular biology 32 16107689
2012 Detection of variants in SLC6A8 and functional analysis of unclassified missense variants. Molecular genetics and metabolism 30 22281021
2014 Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clinical genetics 28 24597975
2014 Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1. Kidney & blood pressure research 28 25531585
2008 Detection of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency. Neurogenetics 28 18350323
2014 Creatine transporter (SLC6A8) knockout mice display an increased capacity for in vitro creatine biosynthesis in skeletal muscle. Frontiers in physiology 27 25206338
1996 The genomic organization of a human creatine transporter (CRTR) gene located in Xq28. Genomics 27 8661155
2018 Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8. Genes, brain, and behavior 26 29384270
2015 Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene. Gene 26 25861866
2007 Mental retardation and verbal dyspraxia in a new patient with de novo creatine transporter (SLC6A8) mutation. American journal of medical genetics. Part A 26 17603797
2010 Overexpression of CrtR-b2 (carotene beta hydroxylase 2) from S. lycopersicum L. differentially affects xanthophyll synthesis and accumulation in transgenic tomato plants. Transgenic research 23 20383744
2005 X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation. Neurogenetics 23 16086185
2018 Mutations in Caenorhabditis elegans neuroligin-like glit-1, the apoptosis pathway and the calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-OHDA treatment. PLoS genetics 22 29346364
2021 SLC6A8 is involved in the progression of non-small cell lung cancer through the Notch signaling pathway. Annals of translational medicine 21 33708891
2020 Classification of the Molecular Defects Associated with Pathogenic Variants of the SLC6A8 Creatine Transporter. Biochemistry 20 32207963
2012 Downregulation of the creatine transporter SLC6A8 by JAK2. The Journal of membrane biology 20 22407360
2010 Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene. Molecular genetics and metabolism 20 21144783
2014 Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature. American journal of medical genetics. Part A 19 25044748
2012 Modeling the interfacial interactions between CrtS and CrtR from Xanthophyllomyces dendrorhous , a P450 system involved in astaxanthin production. Journal of agricultural and food chemistry 19 22897793
2011 Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1. European journal of human genetics : EJHG 19 21267006
2010 Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database. European journal of human genetics : EJHG 18 20717164
2019 Biopriming of maize germination by the plant growth-promoting rhizobacterium Azospirillum lipoferum CRT1. Journal of plant physiology 17 31071544
2019 Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness. Behavioural brain research 16 31542396
2013 Urine screening for patients with developmental disabilities detected a patient with creatine transporter deficiency due to a novel missense mutation in SLC6A8. Brain & development 16 24045174
2012 Functional and electrophysiological characterization of four non-truncating mutations responsible for creatine transporter (SLC6A8) deficiency syndrome. Journal of inherited metabolic disease 16 22644605
1999 The dimerization/repression domain of RFX1 is related to a conserved region of its yeast homologues Crt1 and Sak1: a new function for an ancient motif. Journal of molecular biology 16 10556033
2020 Corynebacterium glutamicum CrtR and Its Orthologs in Actinobacteria: Conserved Function and Application as Genetically Encoded Biosensor for Detection of Geranylgeranyl Pyrophosphate. International journal of molecular sciences 15 32751941
2015 Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by the Janus Kinase JAK3. Neuro-Signals 13 26666525
2023 Experimental and Computational Analysis of Newly Identified Pathogenic Mutations in the Creatine Transporter SLC6A8. Journal of molecular biology 12 38070861
2018 A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report. BMC medical genetics 12 30400883
2010 Applicability of the 16S-23S rDNA internal spacer for PCR detection of the phytostimulatory PGPR inoculant Azospirillum lipoferum CRT1 in field soil. Journal of applied microbiology 12 19583800
2022 Functional Characterization of Sugar Transporter CRT1 Reveals Differential Roles of Its C-Terminal Region in Sugar Transport and Cellulase Induction in Trichoderma reesei. Microbiology spectrum 10 35852347
2013 A Novel SLC6A8 Mutation in a Large Family with X-Linked Intellectual Disability: Clinical and Proton Magnetic Resonance Spectroscopy Data of Both Hemizygous Males and Heterozygous Females. JIMD reports 10 24190795
2010 Modulation of CP2 family transcriptional activity by CRTR-1 and sumoylation. PloS one 10 20661472
2020 Cyclocreatine Transport by SLC6A8, the Creatine Transporter, in HEK293 Cells, a Human Blood-Brain Barrier Model Cell, and CCDSs Patient-Derived Fibroblasts. Pharmaceutical research 9 32124083
2020 Nanosecond pulsed electric fields modulate the expression of the astaxanthin biosynthesis genes psy, crtR-b and bkt 1 in Haematococcus pluvialis. Scientific reports 9 32968095
2019 Deletion of the Creatine Transporter (Slc6a8) in Dopaminergic Neurons Leads to Hyperactivity in Mice. Journal of molecular neuroscience : MN 9 31520365
2024 ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes. Molecular genetics and metabolism 8 38452609
2024 Novel Corrector for Variants of SLC6A8: A Therapeutic Opportunity for Creatine Transporter Deficiency. ACS chemical biology 8 39418577
2014 RNA sequencing of creatine transporter (SLC6A8) deficient fibroblasts reveals impairment of the extracellular matrix. Human mutation 8 24962355
2021 Treatment efficacy of high-dose creatine supplementation in a child with creatine transporter (SLC6A8) deficiency. Molecular genetics & genomic medicine 7 33656256
2023 CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport. Oncoimmunology 6 37089447
2006 Overexpression of wild-type creatine transporter (SLC6A8) restores creatine uptake in primary SLC6A8-deficient fibroblasts. Journal of inherited metabolic disease 6 16763899
2016 Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3ß. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 5 27978525
2022 Identification of novel variations in SLC6A8 and GAMT genes causing cerebral creatine deficiency syndrome. Clinica chimica acta; international journal of clinical chemistry 4 35588794
2020 Determination of Intrinsic Creatine Transporter (Slc6a8) Activity and Creatine Transport Function of Leukocytes in Rats. Biological & pharmaceutical bulletin 4 32115505
2015 A novel SLC6A8 mutation associated with motor dysfunction in a child exhibiting creatine transporter deficiency. Human genome variation 4 27081545
2025 Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy. Cell death & disease 3 39952955
2024 Intestinal Epithelial Creatine Transporter SLC6A8 Dysregulation in Inflammation and in Response to Adherent Invasive E. coli Infection. International journal of molecular sciences 3 38928243
2023 Characterization of seizures and EEG findings in creatine transporter deficiency due to SLC6A8 mutation. American journal of medical genetics. Part A 3 37850681
2018 Functional assessment of creatine transporter in control and X-linked SLC6A8-deficient fibroblasts. Molecular genetics and metabolism 3 29478817
2011 Molecular analysis of guanidinoacetate-n-methyltransferase (GAMT) and creatine transporter (SLC6A8) gene by using denaturing high pressure liquid chromatography (DHPLC) as a possible source of human male infertility. Pakistan journal of pharmaceutical sciences 3 21190923
2025 Calreticulin (crt-1) silencing reduces Aß1-42-induced toxicity and restores muscle function in C. elegans. Biochimica et biophysica acta. Molecular basis of disease 2 40473085
2024 Upregulation and epigenetic modification of the creatine transporter SLC6A8 in non-small cell lung cancer. Histology and histopathology 2 38529720
2022 Pan-Cancer Analysis of the Oncogenic and Immunological Role of Solute Carrier Family 6 Member 8 (SLC6A8). Frontiers in genetics 2 36061183
2025 [18F]FDG-PET and [18F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation. Scientific reports 1 40025148
2025 Effects of SLC6A8 mutation-induced creatine deficiency on cellular function in fibroblasts. Scientific reports 1 40702043
2025 SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer. Cell reports 1 40892544
2024 Molecular Mechanism of SLC6A8 Dysfunction with c.1699T > C (p.S567P) Mutation in Cerebral Creatine Deficiency Syndromes. Biological & pharmaceutical bulletin 1 38233148
2020 [Clinical features and SLC6A8 gene mutations of cerebral creatine deficiency syndrome I: an analysis of two families]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 1 32434645
2026 A mouse model of a patient derived P544L mutation in the Slc6a8 gene shows hypoactivity and cognitive deficits. Brain research 0 41500337
2026 Targeting SLC6A8 suppresses tumor growth and enhances ferroptosis in hepatocellular carcinoma. Journal of cancer research and clinical oncology 0 41787198
2026 The Transcriptional Regulator Crt1 is Involved in The Pathogenic Lifestyle of Xanthomonas campestris pv. campestris B100. Polish journal of microbiology 0 41943408
2025 Multiple machine learning algorithms identified SLC6A8 as a diagnostic biomarker of the late stage of Hepatocellular carcinoma. Discover oncology 0 40240560
2024 Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8. Molecular genetics and metabolism 0 39418753
2024 [Clinical characterisation of creatine transporter deficiency associated with SLC6A8 gene variants]. Zhonghua er ke za zhi = Chinese journal of pediatrics 0 39563050
2023 [Clinical and genetic analysis of a child with Cerebral creatine deficiency syndrome due to variant of SLC6A8 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 37906149

Missed literature

Know a paper Affinage missed for SLC6A8? Flag it for the maintainers and the community.

No submissions yet.