Affinage

SLC16A2

Monocarboxylate transporter 8 · UniProt P36021

Length
539 aa
Mass
59.5 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC16A2 (MCT8) is a twelve-transmembrane-domain facilitated transporter that mediates bidirectional, Na⁺-independent cellular uptake and efflux of thyroid hormones — principally T3 and T4, but also rT3 and 3,3′-T2 — and is the dominant thyroid hormone transporter at the blood–brain barrier, in neurons, oligodendrocyte progenitors, and skeletal muscle satellite cells (PMID:15889350, PMID:18687783, PMID:19641107, PMID:27664134, PMID:29706500). Substrate recognition within the transport channel depends on a His192–His415–Arg301 clamp and a functionally paired Arg445–Asp498 charge relay, while loss-of-function mutations impair transport through three mechanisms: reduced protein stability, defective trafficking to the plasma membrane, or diminished substrate affinity (PMID:23592749, PMID:24265446, PMID:18187543, PMID:23550058). At the blood–brain barrier, MCT8 is the rate-limiting gateway for T3 entry; its absence causes brain thyroid hormone deficiency with impaired myelination, Purkinje cell differentiation, neural stem cell proliferation, and neurovascular integrity, while peripheral tissues exhibit thyrotoxicosis — the hallmark of Allan–Herndon–Dudley syndrome (PMID:24691440, PMID:37924081, PMID:15889350, PMID:38376950). The thyroid hormone analogues TRIAC and DITPA bypass MCT8 to reach neural cells, providing a pharmacological rationale for treatment of MCT8-deficient patients (PMID:25389909, PMID:38376950).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 Medium

    The initial cloning of SLC16A2 (XPCT) established it as a twelve-transmembrane-domain protein with transporter-family topology, providing the structural framework for subsequent functional characterization.

    Evidence Positional cloning with hydropathy-based structural prediction from the X chromosome

    PMID:7981683

    Open questions at the time
    • No transport substrate identified
    • Single study without functional assay
    • Predicted topology not experimentally validated
  2. 2005 High

    Identification of inactivating MCT8 mutations in families with Allan–Herndon–Dudley syndrome, together with in vitro transport assays, established MCT8 as a specific T3 transporter whose loss causes elevated serum T3 and reduced T4, linking the gene to a Mendelian neurological disorder.

    Evidence Mutation analysis in six AHDS families; ¹²⁵I-T3 uptake assays and immunolocalization of wild-type and mutant MCT8 in transfected cells

    PMID:15889350 PMID:15980113 PMID:16131597

    Open questions at the time
    • Mechanism of neurological damage not yet resolved
    • T4 transport by MCT8 not yet characterized
    • In vivo tissue-specific requirements unknown
  3. 2008 High

    Systematic characterization of patient-derived mutations revealed three distinct loss-of-function mechanisms — reduced expression, impaired trafficking, and reduced substrate affinity — and showed that MCT8 localizes to blood–brain barrier endothelium (luminal and abluminal) and choroid plexus apically, positioning it as the brain's thyroid hormone gatekeeper.

    Evidence Affinity labeling, Western blot, immunocytochemistry of mutants in JEG3/COS1 cells; protein immunolocalization in human/mouse/rat brain microvasculature and choroid plexus

    PMID:18187543 PMID:18687783

    Open questions at the time
    • Why human neurons are more vulnerable than mouse neurons not yet explained
    • Structural basis of substrate translocation unknown
  4. 2009 High

    Transport assays in primary neurons and patient fibroblasts demonstrated that MCT8 mediates both T3 uptake and efflux, that LAT2 provides functional compensation in mouse but not human neurons, and that trafficking and function of MCT8 mutants are cell-type dependent.

    Evidence Primary cortical neuron uptake assays with pharmacological dissection; bidirectional transport in patient fibroblasts; surface biotinylation in JEG1 vs MDCK1 cells

    PMID:18636565 PMID:19641107 PMID:19648159

    Open questions at the time
    • Identity of cell-type-specific trafficking cofactors unknown
    • In vivo significance of bidirectional transport not tested
  5. 2010 High

    Discovery that retinoic acid transcriptionally induces MCT8 expression >300-fold through a RAR/RXR-binding element upstream of the gene established a transcriptional regulatory axis for MCT8.

    Evidence ChIP for RAR/RXR binding, promoter-reporter assay, T3/T4 uptake after RA treatment in F9 cells

    PMID:20573951

    Open questions at the time
    • Physiological relevance during brain development not tested in vivo
    • Other transcriptional regulators not mapped
  6. 2013 High

    Site-directed mutagenesis and chemical modification identified a substrate recognition mechanism comprising His192, His415, Arg301, Arg445, and Asp498 within the transmembrane channel, with a His–Arg clamp analogous to the thyroid hormone receptor and a functionally essential Arg445–Asp498 charge pair.

    Evidence DEPC modification with substrate protection; charge-swap double mutants; transport kinetics in MDCK1 cells and Xenopus oocytes; homology modeling

    PMID:23592749 PMID:23610131 PMID:24265446

    Open questions at the time
    • No high-resolution experimental structure
    • Conformational cycle (inward-open to outward-open) not characterized
    • Residues governing T3 vs T4 selectivity not identified
  7. 2012 High

    Identification of PTTG1IP (PBF) as a physical interactor that redirects MCT8 away from the plasma membrane provided the first named protein partner that regulates MCT8 surface availability.

    Evidence Co-immunoprecipitation/pulldown; surface biotinylation; PBF-transgenic mouse thyroid phenocopy of Mct8 KO

    PMID:22535767

    Open questions at the time
    • Binding interface not mapped
    • Whether PBF regulates MCT8 at the BBB unknown
    • Other trafficking regulators not identified
  8. 2014 High

    The Mct8/Oatp1c1 double-knockout mouse established that combined loss of both brain thyroid hormone transporters is required to recapitulate human AHDS neuropathology — including cerebellar delay, hypomyelination, and GABAergic interneuron defects — explaining why single Mct8 KO mice lack a brain phenotype.

    Evidence DKO mouse generation; brain TH content, deiodinase activity, histology, behavioral testing

    PMID:24691440

    Open questions at the time
    • Relative contributions of individual cell types (neuron vs glia vs endothelium) not dissected
    • Postnatal rescue window not defined
  9. 2016 High

    BBB-targeted MCT8 re-expression (by AAV9 IV injection in mice and BBB-endothelial transgene in zebrafish) was sufficient to restore brain T3 content and rescue hypomyelination, proving that MCT8 at the blood–brain barrier is the critical site for brain thyroid hormone supply; separately, chemical chaperone NaPB rescued destabilized MCT8 mutants, and silychristin was identified as a nanomolar-potency MCT8-specific inhibitor.

    Evidence AAV9-MCT8 IV/ICV injection in Mct8 KO mice; BBB-targeted Mct8-tagRFP transgenic rescue in mct8⁻/⁻ zebrafish; NaPB dose–response with kinetic analysis in MDCK cells; silychristin IC₅₀ determination

    PMID:26910310 PMID:27432638 PMID:27664134 PMID:27977298

    Open questions at the time
    • Long-term neurological rescue not assessed
    • NaPB efficacy in vivo not demonstrated
    • Silychristin mechanism of inhibition not defined
  10. 2016 High

    TRIAC was shown to bypass MCT8, entering neurons and OPCs via alternative transporters and restoring TH-dependent differentiation in MCT8-deficient models, providing a pharmacological bypass strategy.

    Evidence Radiolabeled transport assays in MCT8-deficient cells; in vivo TRIAC treatment of Mct8/Oatp1c1-DKO mice; RNAi of MCT8 in chicken cerebellum with TRIAC rescue

    PMID:25389909 PMID:27879339

    Open questions at the time
    • TRIAC efficacy in human clinical trials not yet fully evaluated
    • Alternative transporter identity for TRIAC not definitively established
  11. 2021 High

    Cell-type-specific conditional knockouts extended MCT8's functional role beyond neurons and glia to adult neural stem cells and bone cells, showing that MCT8-mediated T3 uptake cell-autonomously controls NSC proliferation/neuronal fate and osteoblast-osteoclast homeostasis.

    Evidence Mct8/Oatp1c1 DKO SVZ analysis with BrdU and fate markers; conditional Mct8 KO in osteoprogenitors with bone microarchitecture and ex vivo T3 uptake

    PMID:31910109 PMID:33450189

    Open questions at the time
    • Whether skeletal phenotype contributes to AHDS morbidity unknown
    • Signaling pathways downstream of T3 in NSCs not mapped
  12. 2023 High

    MCT8 deficiency was found to compromise blood–brain barrier structural integrity itself — causing increased transcytosis, IgG leakage, and reduced vessel density — revealing a neurovascular dimension of AHDS pathology beyond simple T3 deprivation.

    Evidence TEM of BBB, sodium fluorescein/Evans Blue infiltration, IgG immunohistochemistry, MR angiography in Mct8/Dio2 KO mice and human AHDS brain sections

    PMID:37924081

    Open questions at the time
    • Whether BBB leakage is a direct consequence of local T3 deficiency or an independent MCT8 function is unclear
    • Reversibility of BBB damage not tested
  13. 2024 High

    Human iPSC-derived cerebral organoids from AHDS patients confirmed that MCT8 deficiency impairs T3 transport into developing neural tissue and reduces cortical development, and validated TRIAC and DITPA as compounds that restore TH-responsive gene expression independently of MCT8.

    Evidence Patient iPSC-derived cerebral organoids; D3-mediated T3 catabolism transport assay; gene expression profiling; TH analog rescue

    PMID:38376950

    Open questions at the time
    • Long-term cortical maturation in organoids not assessed
    • Whether early prenatal treatment could prevent human AHDS neuropathology remains unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of MCT8, the conformational mechanism of substrate translocation, the identity of cell-type-specific trafficking cofactors that modulate MCT8 surface expression, and the therapeutic window for brain-targeted MCT8 gene therapy or TH analog treatment in AHDS patients.
  • No experimental three-dimensional structure solved
  • Conformational cycle during transport not characterized
  • Optimal postnatal therapeutic window for neurological rescue not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7
Localization
GO:0005886 plasma membrane 6 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-382551 Transport of small molecules 6 R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 5
Partners
PTTG1IPSLCO1C1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 SLC16A2 (then called XPCT) encodes a predicted 67 kDa protein containing twelve hydrophobic transmembrane domains characteristic of transporter proteins, with an N-terminal PEST domain, and is subject to X chromosome inactivation despite proximity to XIST. Positional cloning, expression studies, structural prediction Human molecular genetics Medium 7981683
2005 MCT8 (SLC16A2) functions as a specific transporter of triiodothyronine (T3) into neurons; inactivating mutations cause elevated free T3 and lowered free T4 in blood, indicating loss of T3 transport function. Mutation analysis in six families with Allan-Herndon-Dudley syndrome, biochemical thyroid hormone measurements American journal of human genetics High 15889350
2005 The MCT8 A150V missense mutation in transmembrane domain 2 abolishes T3 uptake and causes intracellular retention of the protein rather than plasma membrane expression; wild-type MCT8 forms multimers. 125I-T3 uptake assay, immunofluorescence, dimerization studies in transfected cells European journal of endocrinology High 16131597
2005 A frameshift MCT8 mutation (c.1834delC) decreases cellular T3 uptake and intracellular T3 metabolism, demonstrating that MCT8 is required for both substrate entry and subsequent metabolism by deiodinases. In vitro T3 uptake assay and T3 metabolism assay in transfected cells Journal of medical genetics High 15980113
2008 MCT8 mutations cause loss of thyroid hormone transport function through three distinct mechanisms: reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity; mutants with residual transport activity (L434W, L568P, S194F, ~20–37% of WT) correlate with milder psychomotor phenotype. T3/T4 uptake assay, T3 metabolism assay, Western blotting, affinity labeling with N-bromoacetyl-T3, immunocytochemistry, quantitative RT-PCR in transfected JEG3 and COS1 cells Endocrinology High 18187543
2008 MCT8 mRNA and protein are expressed in cerebral microvessels (blood-brain barrier) in human, mouse, and rat in addition to neurons; in rat, Mct8 localizes to both luminal and abluminal microvessel membranes; in choroid plexus MCT8 is concentrated on the apical surface. mRNA expression analysis, protein immunolocalization in cerebral microvessels and choroid plexus of human, mouse, and rat Endocrinology High 18687783
2009 The majority of T3 uptake in primary cortical neurons is mediated by Mct8; pharmacological inhibition and mRNA profiling show that L-type amino acid transporters (LATs, including Lat2) are co-expressed in mouse neurons and provide functional complementation in Mct8-deficient mice but not in developing human neurons where LAT2 is expressed in microglia rather than neurons. Primary cortical neuron T3 uptake assay, pharmacological inhibition, mRNA profiling, immunolocalization in murine and human brain The Journal of neuroscience High 19641107
2009 MCT8 mutations can impair both T3 uptake and T3 efflux in patient fibroblasts; the F501del mutation causes a milder phenotype because it reduces T3 uptake only modestly while strongly reducing T3 efflux, potentially retaining T3 in cells. T3 uptake and efflux assays in patient-derived fibroblasts, type 3 deiodinase activity measurements, T3-responsive gene expression analysis Human mutation High 18636565
2009 Functional activity and plasma membrane surface translocation of MCT8 missense mutants (e.g., ins235V, L568P, R271H) are cell-type dependent, suggesting tissue-specific interacting proteins influence MCT8 trafficking and function. Stable cell lines in JEG1 and MDCK1 cells: T3 transport assay, surface biotinylation, kinetic analysis, immunocytochemistry Journal of molecular endocrinology High 19648159
2011 Tyrosine kinase inhibitors (sunitinib, imatinib, dasatinib, bosutinib) dose-dependently inhibit MCT8-mediated T3 and T4 uptake in a noncompetitive manner, with IC50 values of 13–38 µM. 125I-T3 uptake and efflux assay in MDCK1 cells stably expressing human MCT8; kinetic analysis of inhibition mode The Journal of clinical endocrinology and metabolism High 22031512
2011 Zebrafish Slc16a2 (Mct8) transports T3 in a saturable, Na+-independent, temperature-dependent manner (Km ~0.8 µM at 26°C); at 26°C it does not transport T4, but does so at 37°C; it is highly expressed in brain, gills, pancreas, liver, pituitary, and heart, and expressed from mid-blastula stage. Cloning, heterologous expression, 125I-T3 uptake kinetics in transfected cells; tissue expression by qPCR Endocrinology High 21952246
2012 PTTG-binding factor (PBF/PTTG1IP) physically binds MCT8 in vitro (co-immunoprecipitation/pulldown), shifts MCT8 subcellular localization away from the plasma membrane, and reduces MCT8 surface expression; PBF overexpression in mouse thyroid in vivo causes enhanced thyroidal TH accumulation and reduced TH secretion, phenocopying Mct8 knockout. Co-IP/pulldown, cell surface biotinylation assay, immunolocalization in PBF-transgenic mice, thyroid TH accumulation assay Endocrinology High 22535767
2013 Arg445 (TM8) and Asp498 (TM10) of MCT8 are critical for thyroid hormone transport; mutations altering the charge at either position nearly abolish TH uptake without affecting protein expression, stability, or localization; charge-exchange double mutant (R445D+D498R) partially restores T4 uptake, indicating a functionally important charge pair between these residues. Site-directed mutagenesis, T3/T4 uptake assay, Western blotting, confocal microscopy in transfected cells Endocrinology High 24265446
2013 His192, located at the border of TM1 and ECL1, is critical for TH uptake: DEPC modification of His residues inhibits T3/T4 uptake (but not efflux), and this inhibition is blocked by pre-incubation with substrate; H192A mutation reduces TH uptake and abolishes DEPC sensitivity, placing His192 near the substrate recognition site. Chemical modification with DEPC, site-directed mutagenesis (H192A, H260A, H450A), T3/T4 uptake assay in transfected cells Endocrinology High 23610131
2013 His192 and His415, together with Arg301, form a substrate recognition motif within the MCT8 transport channel; mutations at His192, His415, and Arg301 significantly alter substrate transport kinetics; molecular modeling places T3 between His415 and Arg301 analogous to the His-Arg clamp in the T3 receptor. Site-directed mutagenesis, T3 transport kinetics in MDCK-1 cells and Xenopus oocytes, molecular modeling Endocrinology High 23592749
2013 MCT8 mutations can be classified into two mechanistic groups: those causing partial or complete loss of transport activity while retaining plasma membrane localization (G221R, P321L, D453V, P537L), and those that mainly disrupt protein expression and trafficking causing ER retention (insV236, G282C, G558D). Live-cell imaging of MCT8-CFP fusion constructs in Flp-in 293 cells, T3/T4 uptake assay in multiple cell types, FRAP analysis Molecular endocrinology High 23550058
2013 Mct10 (Slc16a10) facilitates thyroid hormone efflux from liver and kidney, contributing to the elevated serum T4 phenotype of Mct8-deficient mice; Mct10/Mct8 double knockout partially restores serum T4 levels compared with Mct8 single KO, demonstrating that Mct10 contributes to TH efflux from peripheral tissues in vivo. Mct10 KO and Mct8/Mct10 double KO mouse generation; serum TH measurements, tissue TH content analysis Endocrinology High 24248460
2014 Combined deficiency of MCT8 and OATP1C1 in mice strongly reduces brain uptake of both T3 and T4, causing cerebral hypothyroidism, delayed cerebellar development, reduced myelination, and compromised differentiation of GABAergic interneurons; single Mct8 KO mice do not show these neurological phenotypes because residual T4 entry via OATP1C1 compensates. Mct8/Oatp1c1 double KO mouse generation; brain TH content, deiodinase activity, TH target gene expression, histological and behavioral analysis The Journal of clinical investigation High 24691440
2014 Triiodothyroacetic acid (TRIAC/TA3) is not significantly transported by MCT8; it bypasses MCT8 in neuronal and oligodendrocyte cell lines and in patient fibroblasts, and can replace T3 to promote neural differentiation in cerebellum and cerebral cortex of MCT8-deficient mice. Radiolabeled substrate uptake in SH-SY5Y and MO3.13 cells and patient fibroblasts; TRIAC transport assay in MCT8-transfected cells; in vivo treatment of Pax8-KO and Mct8/Oatp1c1-DKO mice with assessment of TH-dependent gene expression and cerebellar/cortical development Molecular endocrinology High 25389909
2010 Retinoic acid (RA), acting through retinoic acid receptor (RAR) binding to a consensus RA-response element 6.6 kb upstream of the Mct8 coding region, transcriptionally induces Mct8 expression >300-fold in F9 cells, increasing T3 and T4 uptake; this was abolished by a selective MCT8 inhibitor. Promoter-reporter assay, chromatin immunoprecipitation (RAR/RXR binding), T3/T4 uptake assay, pharmacological inhibition in F9 cells The Journal of biological chemistry High 20573951
2016 Silychristin (a flavonolignan from milk thistle) inhibits MCT8-mediated T3 uptake with an IC50 of ~100 nM, at least 1 order of magnitude below other known MCT8 inhibitors, and shows specificity for MCT8 over MCT10 in overexpressing cells and endogenous Mct8 in primary murine astrocytes. Non-radioactive T3 uptake assay in MCT8-overexpressing MDCK1 cells and primary murine astrocytes; IC50 determination; MCT10-specificity control Endocrinology High 26910310
2016 AAV9-mediated delivery of human MCT8 to brain barriers via intravenous (but not intracerebroventricular) injection in Mct8 KO mice increases brain T3 content and expression of T3-responsive genes (Hairless), demonstrating that MCT8 at brain barriers (including choroid plexus) is the critical site for T3 entry into the brain. IV and ICV AAV9 injection in Mct8 KO mice; brain T3 content measurement, Hairless gene expression, MCT8 protein localization by immunohistochemistry Thyroid High 27432638
2016 Chemical chaperone sodium phenylbutyrate (NaPB) rescues protein expression and transport function of several destabilized MCT8 mutants (S194F, S290F, L434W, R445C, L492P, L568P, delF501) in a dose-dependent manner; kinetic analysis shows these mutants have near-normal substrate affinity (Km for T3), indicating destabilization rather than active-site disruption as the primary defect. NaPB treatment of MDCK cells stably expressing MCT8 mutants; T3 transport assay, protein expression analysis, kinetic analysis Endocrinology High 27977298
2018 MCT8 and OATP1C1 are expressed in activated skeletal muscle satellite cells (SCs) and act as gatekeepers of TH entry; Mct8/Oatp1c1 double KO mice show strongly reduced SC differentiation and impaired skeletal muscle regeneration, phenocopied by SC-specific conditional double KO. Conditional and global double KO mice; SC isolation; tissue TH content; TH-regulated gene expression; muscle regeneration assay Stem cell reports High 29706500
2016 In mct8-deficient zebrafish, MCT8 is required for oligodendrocyte progenitor cell (OPC) differentiation into mature oligodendrocytes; mosaic expression of Mct8-tagRFP specifically in blood-brain barrier endothelial cells completely rescued CNS hypomyelination, demonstrating that MCT8 at the BBB is sufficient to restore myelination. mct8-/- zebrafish model; quantification of OPC and oligodendrocyte markers; live imaging of glial cells; BBB-targeted transgenic rescue with Mct8-tagRFP Disease models & mechanisms High 27664134
2016 MCT8 deficiency in Purkinje cell precursors (via RNAi electroporation in chicken embryo) causes cell-autonomous defects: downregulation of TH-responsive gene RORα and Purkinje cell marker LHX1/5, reduced dendritic complexity; and non-autonomous effects on granule cell precursor proliferation and radial migration. MCT8-RNAi electroporation into chicken cerebellar anlage; immunostaining for differentiation markers; TRIAC rescue experiment The Journal of endocrinology High 27879339
2019 Human, mouse, and zebrafish MCT8 orthologues all transport T3, T4, rT3, and 3,3'-T2 by facilitated diffusion; zebrafish Mct8 has 1.5–4-fold higher initial uptake rates and 3–50-fold lower IC50 values for substrates than human or mouse MCT8, with different substrate preference; His192 in human MCT8, replaced by Gln in zebrafish, does not underlie these kinetic differences. Comparative transport assays in transiently transfected COS-1 and JEG-3 cells; surface biotinylation; immunoblotting; structural modeling; H192Q mutagenesis Thyroid High 31436139
2021 Both MCT8 and OATP1C1 are expressed in adult mouse subventricular zone neural stem cells (NSCs); Mct8/Oatp1c1 double KO severely impairs NSC proliferation and neuronal fate determination but not oligodendrocyte progenitor generation, identifying TH transport as a regulator of NSC function and glial-neuron cell fate in the adult brain. Immunohistochemical localization of MCT8/OATP1C1 in SVZ; analysis of Mct8/Oatp1c1 DKO mice for NSC proliferation (BrdU), fate markers, and progenitor numbers Stem cell reports High 33450189
2021 MCT8 in osteoblast and osteoclast progenitors mediates T3 uptake in a cell-intrinsic manner; conditional Mct8 KO in osteoprogenitors increases trabecular bone volume and alters osteoblast/osteoclast numbers independently of systemic T3 elevation. Conditional Mct8 KO mouse lines targeting osteoclast precursors, osteoprogenitors, and mature osteoblasts/osteocytes; bone microarchitecture, turnover, ex vivo T3 uptake in bone marrow-derived cells Thyroid High 31910109
2024 MCT8-deficient human cerebral organoids (from patient iPSCs) show impaired T3 transport into developing neural cells (assessed by deiodinase-3-mediated T3 catabolism assay), smaller neural rosettes with thinner cortical units, reduced cortex development gene expression, and reduced T3-inducibility of TH-regulated genes; TH analogs DITPA and TRIAC bypass MCT8 and restore normal TH-responsive gene induction. Human iPSC-derived cerebral organoids from MCT8-deficient patients; D3-mediated T3 catabolism as transport proxy; gene expression analysis; TH analog rescue experiments JCI insight High 38376950
2016 MCT8 mediates TH transport and is required for TH-dependent OPC maturation in a cell-autonomous manner; MCT8-deficient iPSC-derived OPCs transplanted into a hypothyroid triple KO mouse (mct8-/-; oatp1c1-/-; rag2-/-) fail to mature into oligodendrocytes, demonstrating that functional TH transport across brain barriers is also required for in vivo oligodendrocyte maturation. iPSC differentiation to OPCs; transplantation into shiverer and hypothyroid triple KO mice; behavioral and myelination assessment Glia High 33956384
2023 MCT8 deficiency (in Mct8/Dio2 KO mice and in human AHDS brain tissue) causes neurovascular unit disruption and blood-brain barrier leakage, including increased transcytosis, IgG extravasation, and reduced brain vessel density, identifying BBB structural integrity as an additional MCT8-dependent mechanism. Transmission electron microscopy of BBB; non-permeable dye (sodium fluorescein, Evans Blue) infiltration assays; IgG immunohistochemistry; MR angiography; angiogenesis gene expression by qRT-PCR in Mct8/Dio2KO mice and human AHDS brain sections Fluids and barriers of the CNS High 37924081

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. American journal of human genetics 287 15889350
2008 Expression of the thyroid hormone transporters monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier. Endocrinology 268 18687783
2014 Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. The Journal of clinical investigation 220 24691440
2009 Neuronal 3',3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 163 19641107
2014 Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination. The Journal of clinical endocrinology and metabolism 126 25222753
2007 The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. Best practice & research. Clinical endocrinology & metabolism 111 17574010
2012 Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. The Journal of clinical endocrinology and metabolism 104 22993035
2010 Genetics and phenomics of thyroid hormone transport by MCT8. Molecular and cellular endocrinology 95 20083155
2009 Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters. Journal of molecular endocrinology 94 19541799
1994 A novel transmembrane transporter encoded by the XPCT gene in Xq13.2. Human molecular genetics 94 7981683
2020 Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study. The lancet. Diabetes & endocrinology 90 32559475
2009 Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects. Annals of neurology 80 19194886
2005 Extended clinical phenotype, endocrine investigations and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter MCT8. European journal of endocrinology 79 16131597
2014 In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. Molecular endocrinology (Baltimore, Md.) 76 25389909
2008 Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8. Endocrinology 76 18187543
2011 Tyrosine kinase inhibitors noncompetitively inhibit MCT8-mediated iodothyronine transport. The Journal of clinical endocrinology and metabolism 75 22031512
2007 Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter. European journal of pediatrics 73 17899191
2006 Distribution of monocarboxylate transporters MCT1-MCT8 in rat tissues and human skeletal muscle. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 73 16604139
2013 Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency. Endocrinology 71 24248460
2008 Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8. The Journal of clinical endocrinology and metabolism 71 18334584
2019 Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations. Developmental medicine and child neurology 69 31410843
2005 X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype. Journal of child neurology 69 16417886
2013 Tetrac can replace thyroid hormone during brain development in mouse mutants deficient in the thyroid hormone transporter mct8. Endocrinology 68 23307789
2011 Identification and functional characterization of zebrafish solute carrier Slc16a2 (Mct8) as a thyroid hormone membrane transporter. Endocrinology 68 21952246
1993 2.6 Mb YAC contig of the human X inactivation center region in Xq13: physical linkage of the RPS4X, PHKA1, XIST and DXS128E genes. Human molecular genetics 63 8401491
2013 Changes in thyroid status during perinatal development of MCT8-deficient male mice. Endocrinology 61 23696569
2011 Distinct roles of deiodinases on the phenotype of Mct8 defect: a comparison of eight different mouse genotypes. Endocrinology 61 21285310
2006 Unexpected peripheral markers of thyroid function in a patient with a novel mutation of the MCT8 thyroid hormone transporter gene. Hormone research 61 16974106
2005 X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene. Journal of neurology 61 15834651
2009 Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations. Human mutation 58 18636565
2016 Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8. Endocrinology 55 26910310
2016 Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish. Disease models & mechanisms 54 27664134
2009 Surface translocation and tri-iodothyronine uptake of mutant MCT8 proteins are cell type-dependent. Journal of molecular endocrinology 54 19648159
2009 White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene. Developmental medicine and child neurology 50 19811520
2008 MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression. European journal of human genetics : EJHG 49 18398436
2005 Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter. Journal of medical genetics 48 15980113
2012 MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. Journal of child neurology 46 22805248
2019 Adult Mice Lacking Mct8 and Dio2 Proteins Present Alterations in Peripheral Thyroid Hormone Levels and Severe Brain and Motor Skill Impairments. Thyroid : official journal of the American Thyroid Association 44 31359845
2022 Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study. The Journal of clinical endocrinology and metabolism 40 34679181
2018 Deafness and loss of cochlear hair cells in the absence of thyroid hormone transporters Slc16a2 (Mct8) and Slc16a10 (Mct10). Scientific reports 39 29535325
2014 MCT8 expression in human fetal cerebral cortex is reduced in severe intrauterine growth restriction. The Journal of endocrinology 39 24204008
2020 MCT8 Deficiency: The Road to Therapies for a Rare Disease. Frontiers in neuroscience 38 32410949
2017 Application of a nonradioactive assay for high throughput screening for inhibition of thyroid hormone uptake via the transmembrane transporter MCT8. Toxicology in vitro : an international journal published in association with BIBRA 38 28119167
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