How does thyroid hormone (TH) find its way into the brain? Although it has been known for a long time that this crucial for normal brain development, the exact molecular mechanisms involved in TH transport in the brain have remained elusive until recently. Early studies showed selective and saturable accumulation of TH in particular brain regions, suggesting that active transport processes are required forTHentry across the blood-brain barrier (BBB) and into brain cells (1). The discovery that TH transporter proteins located in the plasma membrane are required for cellular entry of the hormone has advanced our understanding of TH physiology. Thus, TH transporters mediate transport not only across the BBB but also into each individual cell of the brain.
The mechanism of thyroid hormone (TH) secretion from the thyroid gland into the blood is
unknown. We used the Mct8 deficient mouse (Mct8KO) to determine if MCT8 has a role in this
process. While MCT8 is known to transport TH into cells, several observations suggest that it also
controls TH secretion: (1) Humans and mice deficient in MCT8 have a low serum T4 level, which
cannot be fully explained by increased deiodination; (2) Our preliminary data show that TH
secretion in Mct8KO mice is delayed following the release of endogenous hormone suppression with
methimazole and perchlorate; (3) MCT8 is localized at the basolateral membrane of thyrocytes.
RESULTS: Thyroid glands of Mct8KO mice contained 2.1-fold and 2.3-fold more free T4 and T3 than
wild-type (Wt) mice (P<0.001). This was independent of deiodination as comparable increases were
also found in Mct8KO mice that lacked the types 1 and 2 deiodinases.
This is the fourth newsletter in our series of newsletters on the AHDS or MCT8 deficiency. In this edition, you can read about the progress of the Triac Trial, the genetic basis of the AHDS and much more.
Hypomyelination is a key symptom of the Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8. AHDS is characterized by severe intellectual deficiency, neuromuscular impairment, and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8/-) zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8-/- larvae and adults. Live imaging of single glial cells showed that the number of oligodendrocytes and the length of their extensions are reduced, and the number of peripheral Schwann cells is increased in mct8-/- larvae. Pharmacological analysis showed that TH analogs and clemastine partially rescued the hypomyelination in the CNS of mct8-/- larvae. Intriguingly, triiodothyronine (T3) treatment rescued hypomyelination in mct8-/- embryos before the maturation of the blood-brain barrier (BBB), but did not affect hypomyelination in older larvae. Thus, we expressed Mct8-tagRFP in the endothelial cells of the vascular system and showed that even relatively weak mosaic expression completely rescued hypomyelination in mct8/- larvae. These results suggest potential pharmacological treatments and BBB-targeted gene therapy that can enhance myelination in AHDS and possibly in other THdependent brain disorders.
MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. In this proof of concept study, we examined whether transfer of human MCT8 (hMCT8) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice
The Allan-Herndon-Dudley syndrome (AHDS) is caused by a defect in the thyroid hormone (TH) transporter MCT8 (1,2). The clinical phenotype comprises a “central” component due to impaired psychomotor development with severe intellectual disability, axial hypotonia and dystonia, and a ‘’peripheral’’ component dominated by signs of thyrotoxicosis, caused by elevated serum T3 levels. The combination of high serum T3, low or low-normal serum (F)T4 and normal to modestly elevated serum TSH levels are very typical for AHDS
The evolutionary acquisition of myelin sheaths around large caliber axons in the central nervous system (CNS) represented a milestone in the development of vertebrate higher brain function. Myelin ensheathment of axons enabled salta-tory conduction and thus accelerated information processing. However, a number of CNS diseases harm or destroy myelin and oligodendrocytes (mye-lin-producing cells), ultimately resulting in demyelination. In the adult CNS, new oligodendrocytes can be generated from a quiescent pool of precursor cells, which – upon differentiation – can replace lost myelin sheaths. The efficiency of this spontaneous regeneration is limited, which leads to incomplete remyeli-nation and residual clinical symptoms. Here, we discuss CNS pathologies characterized by white matter degeneration and regeneration and highlight drugs that could potentially serve as remyelination therapies.
Methods
Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter.
Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transmembrane transporter expressed in many cell types, including neurons. Mutations which inactivate transport activity of MCT8 cause severe X-linked psychomotor retardation in male patients, a syndrome originally described as the Allan-Herndon-Dudley syndrome. Treatment options currently explored focus on finding thyroid hormone-like compounds which bypass MCT8 and enter cells through different transporters. Since MCT8 is a multipass transmembrane protein, some pathogenic mutations affect membrane trafficking while potentially retaining some transporter activity.
Objective:
To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I-deiodinase (Dio1).
The cellular influx and efflux of thyroid hormones are facilitated by transmembrane protein transporters. Of these transporters, monocarboxylate transporter 8 (MCT8) is the only one specific for the transport of thyroid hormones and some of their derivatives.
X-linked monocarboxylate transporter 8 (MCT8) deficiency results from a loss-of-function mutation in the monocarboxylate
transporter 8 gene, located on chromosome Xq13.2 (Allan-Herndon-Dudley syndrome). Affected boys present early in life with
neurodevelopment delays but have pleasant dispositions and commonly have elevated serum triiodothyronine.
Monocarboxylate transporter 8 (MCT8) transports thyroid hormone (TH) across the plasma membrane. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome, comprising severe psychomotor retardation and elevated serum T3 levels. Because the neurological symptoms are most likely caused by a lack of TH transport into the central nervous system, the administration of a TH analog that does not require MCT8 for cellular uptake may represent a therapeutic strategy. Here, we investigated the therapeutic potential of the biologically active T3 metabolite Triac (TA3) by studying TA3 transport, metabolism, and action both in vitro and in vivo.
Thyroid hormone is crucial in the development of different organs, particularly the brain. MCT8 is a specific transporter of triiodothyronine (T3) hormone and MCT8 gene mutations cause a rare X-linked disorder named MCT8 deficiency, also known as Allan-Herndon-Dudley syndrome, characterized by psychomotor retardation and hypotonia. Typically, elevation of T3 and delayed myelination in cerebral magnetic resonance imaging are found. Case presentation: We present a 24-month-old boy, born from non-consanguineous healthy parents, with severe motor and cognitive delay and global hypotonia, being unable to hold head upright or sit without support. Deep tendon reflexes were absent bilaterally at the ankles. T3 was elevated and thyroxine slightly decreased, consistent with MCT8 deficiency.
Thyroid hormones (TH) cross the plasma membrane with the help of transporter proteins. As charged amino acid derivatives, TH cannot simply diffuse across a lipid bilayer membrane, despite their notorious hydrophobicity. The identification of monocarboxylate transporter 8 (MCT8, SLC16A2) as a specific and very active TH transporter paved the way to the finding that mutations in the MCT8 gene cause a syndrome of psychomotor retardation in humans. The purpose of this review is to introduce the current model of transmembrane transport and highlight the diversity of TH transmembrane transporters.
The mechanisms and treatment of psychomotor retardation, which includes motor and cognitive impairment, are indefinite. The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked psychomotor retardation characterized by delayed development, severe intellectual disability, muscle hypotonia, and spastic paraplegia, in combination with disturbed thyroid hormone (TH) parameters. AHDS has been associated with mutations in the monocarboxylate transporter 8 (mct8/ slc16a2) gene, which is a TH transporter. In order to determine the pathophysiological mechanisms of AHDS, MCT8 knockout mice were intensively studied. Although these mice faithfully replicated the abnormal serum TH levels, they failed to exhibit the neurological and behavioral symptoms of AHDS patients. Here, we generated an mct8 mutant (mct82/2) zebrafish using zinc-finger nuclease (ZFN) mediated targeted gene editing system.
Patients with the monocarboxylate transporter 8 (MCT8) deficiency syndrome presents with a severe psychomotor retardation and abnormal serum thyroid hormone (TH) levels, consisting of high T3 and low T4 and rT3. Mice deficient in Mct8 replicate the thyroid phenotype of patients with the MCT8 gene mutations. We analyzed the serum TH levels and action in the cerebral cortex and in the liver during the perinatal period of mice deficient in Mct8 to assess how the thyroid abnormalities of Mct8 deficiency develop and to study the thyroidal status of specific tissues. During perinatal life, the thyroid phenotype of Mct8-deficient mice is different from that of adult mice. They manifest hyperthyroxinemia at embryonic day 18 and postnatal day 0. This perinatal hyperthyroxinemia is accompanied by manifestations of TH excess as evidenced by a relative increase in the expression of genes positively regulated by T3 in both the cerebral cortexandliver
MCT8deficiency causes severe X-linked intellectualandneuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analogue diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8 deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8 deficient embryos, in order to determine whether DITPA, when given prenatally, crosses the placenta, and affects the serum TFTs and cerebral cortex of embryos.
Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image.
Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone.
Allan-Herndon-Dudley syndrome, an X-linked condition characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia, is associated with defects in the monocarboxylate transporter 8 gene (MCT8). The long-term prognosis of Allan-Herndon-Dudley syndrome remains uncertain.
Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1).
The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral TH receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology and sought to quantify changes in cortical MCT8 expression with IUGR.
The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression.We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study,we sought to quantify changes in cortical MCT8 expression with IUGR
Children with monocarboxylate transporter 8 (MCT8) deficiency lose weight, even when adequately nourished. Changes in serum markers of thyroid hormone (TH) action compatible with thyrotoxicosis suggested that this might be due to T3 excess in peripheral tissues. Mct8-deficient mice (Mct8KO) replicate the human thyroid phenotype and are thus suitable for metabolic studies so far unavailable in humans. In the current work, compared with wild-type (Wt) mice, Mct8KO mice were leaner due to reduced fat mass. They tended to use more carbohydrates and fewer lipids during the dark phase. Mct8KO mice had increased total energy expenditure (TEE) and food and water intake, with normal total activity, indicating hypermetabolism.
To unravel the role of thyroid hormones (THs) in vertebrate development it is important to have suitable animal models to study the mechanisms regulating TH availability and activity. Zebrafish (Danio rerio), with its rapidly and externally developing transparent embryo has been a widely used model in developmental biology for some time. To date many of the components of the zebrafish thyroid axis have been identified, including the TH transporters MCT8, MCT10 and OATP1C1, the deiodinases D1, D2 and D3, and the receptors TRa and TRb. Their structure and function closely resemble those of higher vertebrates.
Monocarboxylate transporter 8 (MCT8) is a thyroid hormone (TH)-specific transporter. Mutations in the MCT8 gene are associated with Allan-Herndon-Dudley Syndrome (AHDS), consisting of severe psychomotor retardation and disturbed TH parameters. To study the functional consequences of different MCT8 mutations in detail, we combined functional analysis in different cell types with live-cell imaging of the cellular distribution of seven mutations that we identified in patients with AHDS. We used two cell models to study the mutations in vitro: 1) transiently transfected COS1 and JEG3 cells, and 2) stably transfected Flp-in 293 cells expressing a MCT8-cyan fluorescent protein construct.
Allan-Herndon-Dudley syndrome (AHDS), an X linked condition, is characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia in combination with altered TH levels, in particular, high serum T3 levels. Mutations in the MCT8 gene coding for the monocarboxylate thyroid hormone transporter 8 have been associated with AHDS. Here we describe a family with the presence of a MCT8 gene mutation, p.A224T, in three consecutive generations. In two generations its presence was detected in the hemizygous state in two males with neurological abnormalities including mental retardation, axial hypotonia, hypertonia of arms and legs and athetoid movements. One of them presented normal thyroid hormone levels.
The monocarboxylate transporter 8 (MCT8) plays a critical role in mediating the uptake of thyroid hormones (THs) into the brain. In patients, inactivating mutations in the MCT8 gene are associated with a severe form of psychomotor retardation and abnormal serum TH levels. Here, we evaluate the therapeutic potential of the TH analog 3,5,3,5-tetraiodothyroacetic acid (tetrac) as a replacement for T4 in brain development. Using COS1 cells transfected with TH transporter and deiodinase constructs, we could show that tetrac, albeit not being transported by MCT8, can be metabolized to the TH receptor active compound 3,3,5-triiodothyroacetic acid (triac) by type 2 deiodinase and inactivated by type 3 deiodinase.
Allan Herndon Dudley syndrome (AHDS) is a severe psychomotor retardation characterized by neurological impairment and abnormal thyroid hormone (TH) levels. Mutations in the TH transporter, monocarboxylate transporter 8 (MCT8), are associated with AHDS. MCT8-knockout mice exhibit impaired TH levels; however, they lack neurological defects. Here, the zebrafish mct8 gene and promoter were isolated, and mct8 promoter-driven transgenic lines were used to show that, similar to humans, mct8 is primarily expressed in the nervous and vascular systems. Morpholino-based knockdown and rescue experiments revealed that MCT8 is strictly required for neuron development in the brain and spinal cord. This study shows that MCT8 is a crucial regulator during embryonic development and establishes the first vertebrate model for MCT8-deficiency that exhibits a neurological phenotype.
Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked disorder resulting from an impairment of the transcellular transportation of thyroid hormones. Within the central nervous system thyroid hormone transport is normally mediated by MCT8. Patients are described as affected by a static or slowly progressive clinical picture which consists of variable degrees of mental retardation, hypotonia, spasticity, ataxia and involuntary movements, occasionally paroxysmal. The authors describe the clinical and neuroradiological picture of 3 males patients with marked delayed brain myelination and in which the clinical picture was dominated by early onset nonparoxismal extrapyramidal symptoms. In one subject a novel mutation is described.
A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T3 at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient.
Carmen Grijota-Martínez, Diego Díez, Gabriella Morreale de Escobar, Juan Bernal, and Beatriz Morte Abstract: Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon- Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of… Read more: Lack of Action of Exogenously Administered T3 on the Fetal Rat Brain Despite Expression of the Monocarboxylate Transporter 8
Thyroid hormone (TH) is important for the development of different tissues, in particular the brain, as well as for the regulation of the metabolic activities of the tissues and thermogenesis throughout life. Most TH actions are initiated by binding of the active hormone 3,3’,5-triiodothyronine (T3) to its nuclear receptor. This induces an alteration in proteins associated with the transcription initiation complex, resulting in the stimulation or suppression of the expression of TH responsive genes.
Retinoic acid (RA) and thyroid hormone are critical for differentiation and organogenesis in the embryo. Mct8 (monocarboxylate transporter 8), expressed predominantly in the brain and placenta, mediates thyroid hormone uptake from the circulation and is required for normal neural development. RA induces differentiation of F9 mouse teratocarcinoma cells toward neurons as well as extraembryonal endoderm. We hypothesized that Mct8 is functionally expressed in F9 cells and induced by RA. All-trans-RA (tRA) and other RA receptor (RAR) agonists dramatically (>300-fold) induced Mct8. tRA treatment significantly increased uptake of triiodothyronine and thyroxine (4.1- and 4.3-fold, respectively), which was abolished by a selective Mct8 inhibitor, bromosulfophthalein. Sequence inspection of the Mct8 promoter region and 5-rapid amplification of cDNA ends PCR analysis in F9 cells identified 11 transcription start sites and a proximal Sp1 site but no TATA box.
The mechanism of thyroid hormone (TH) secretion from the thyroid gland into blood is unknown. Humans and mice deficient in monocarboxylate transporter 8 (MCT8) have low serum thyroxine (T4) levels that cannot be fully explained by increased deiodination. Here, we have shown that Mct8 is localized at the basolateral membrane of thyrocytes and that the serum TH concentration is reduced in Mct8-KO mice early after being taken off a treatment that almost completely depleted the thyroid gland of TH. Thyroid glands in Mct8-KO mice contained more non-thyroglobulin-associated T4 and triiodothyronine than did those in wild-type mice, independent of deiodination. In addition, depletion of thyroidal TH content was slower during iodine deficiency.
Monocarboxylate transporter 8 (MCT8, SLC16A2) is a thyroid hormone (TH) transmembrane transport protein mutated in Allan-Herndon-Dudley syndrome, a severe Xlinked psychomotor retardation. The neurological and endocrine phenotypes of patients deficient in MCT8 function underscore the physiological significance of carriermediated TH transmembrane transport. MCT8 belongs to the major facilitator superfamily of 12 transmembrane spanning proteins and mediates energy-independent bidirectional transport of iodothyronines across the plasma membrane. Structural information is lacking for all TH transmembrane transporters. In order to gain insight into structure-function relations in TH transport, we chose human MCT8 as paradigm. We systematically performed conventional and liquid chromatographytandem mass spectrometry-based uptake measurements into MCT8-transfected cells using a large number of compounds structurally related to iodothyronines.
Transport of thyroid hormones across the plasma membrane is required for binding to their nuclear receptors. Monocarboxylate transporter 8 (MCT8) is a plasma membrane thyroid hormone transport protein, which has recently gained much attention, since mutations in MCT8 are associated with severe mental retardation in patients afflicted with the Allan- Herndon-Dudley syndrome. MCT8 is expressed along the blood-brain-barrier and on central neurons. We have found that desipramine (DMI), a tricyclic antidepressant, acts as an inhibitor of thyroid hormone transport by MCT8. Uptake of 3,5,3’-triiodo-L-thyronine (T3) into primary cortical neurons could be blocked with desipramine as well as with the known, but unspecific, inhibitor bromosulphtalein (BSP). T3 uptake by neurons derived from Mct8- deficient cells was not further decreased by DMI. In a heterologous expression system, both human MCT8 and its close homolog, MCT10, were sensitive to inhibition by DMI.
Thyroid hormone (TH) induces the dramatic morphological and physiological changes that together comprise amphibian metamorphosis. TH-responsive tissues vary widely with developmental timing of TH-induced changes. How larval tadpole tissues are able to employ distinct metamorphic programs in a developmental stage- and TH-dependent manner is still unknown. Recently, several proteins capable of transporting TH have been identified. TH action and metabolism occurs primarily intracellularly, high- lighting the importance of TH transporters. We examined the hypothesis that TH transporter expression and tissue distribution play an important role in mediating TH-induced metamorphic events.
Theiler’s virus offers a remarkable example of a pathogen that navigates the various cells of the organism to evade immune responses and establish a persistent infection. Here, we discuss the transition from neuron to myelin and oligodendrocyte infection, a step that is crucial for the persistence of this virus in the central nervous system (CNS). CNS myelin is an extension of the cytoplasmic membrane of oligodendrocytes wrapped numerous times around axons. An oligodendrocyte sends many such extensions and can myelinate up to 50 different axons. Myelinated axon segments are separated by short unmyelinated
regions called nodes of Ranvier.
Thyroid hormone is essential for proper brain development since it acts on processes such as neuronal migration and differentiation, myelination and synaptogenesis. In this review, we summarize the consequences of thyroid hormone deficiency for brain development with special focus on the cerebellum, an important target of thyroid action. In addition, we discuss the role of iodothyronine deiodinases and thyroid hormone transporters in regulating local thyroid hormone concentrations as well as current knowledge about the function of thyroid hormone receptors and their target genes during brain maturation.
Mutations of the thyroid hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent.Wetested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given three different doses of DITPA. Effects were compared with treatment with two doses of L-T4. As expected, physiological doses of L-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice.
Mutations of the gene expressing plasma membrane transporter for thyroid hormones MCT8 (SLC16A2) in humans lead to altered thyroid hormone levels and a severe neurodevelopmental disorder. Genetically engineered defect of the Mct8 gene in mice leads to similar thyroid hormone abnormalities, but no obvious impairment of brain development or function. In this work we studied the relative role of the blood-brain barrier, and the neuronal plasma cell membrane in the restricted access of T3 to the target neurons. To this end we compared the effects of low doses of T4 and T3 on cerebellar structure and gene expression in wild type (Wt) and Mct8 null male mice (Mct8-/y, KO) made hypothyroid during the neonatal period. We found that compared to Wt animals, T4 was considerably more potent than T3 in the Mct8KO mice, indicating a restricted access of T3, but not T4, to neurons after systemic administration in vivo.
Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function. Am J Physiol Heart Circ Physiol 296: H1551–H1557, 2009. First published March 13, 2009; doi:10.1152/ajpheart.01293.2008.— Patients with hypothyroidism are at a higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of a healthy vasculature,potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as 3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option.
The mechanism of thyroid hormone (TH) secretion from the thyroid gland into the blood is unknown. We used the Mct8 deficient mouse (Mct8KO) to determine if MCT8 has a role in this process. While MCT8 is known to transport TH into cells, several observations suggest that it also controls TH secretion: (1) Humans and mice deficient in MCT8 have a low serum T4 level, which cannot be fully explained by increased deiodination; (2) Our preliminary data show that TH secretion in Mct8KO mice is delayed following the release of endogenous hormone suppression with methimazole and perchlorate; (3) MCT8 is localized at the basolateral membrane of thyrocytes. RESULTS: Thyroid glands of Mct8KO mice contained 2.1-fold and 2.3-fold more free T4 and T3 than wild-type (Wt) mice (P<0.001).
Pelizaeus–Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus–Merzbacher-Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression.
W. Edward Visser,1 Jurgen Jansen,1 Edith C.H. Friesema,1 Monique H.A. Kester,1 Edna Mancilla,2 Johan Lundgren,3 Marjo S. van der Knaap,4 Roelineke J. Lunsing,5 Oebele F. Brouwer,5 and Theo J. Visser1 Abstract: Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,30,5-triiodothyronine (T3). Mutations in MCT8 are associated with severe psychomotor retardation,… Read more: Novel Pathogenic Mechanism Suggested by Ex Vivo Analysis of MCT8 (SLC16A2) Mutations
In hypothyroid patients, altered microvascular structure and function may affect mood and cognitive function. We hypothesized that adult male hypothyroid rats will have significantly lower forebrain blood vessel densities (BVD) than euthyroid rats and that treatment with 3,5- diiothyroprionic acid (DITPA) (a thyroid hormone analog) or thyroxine (T4) will normalize BVDs. The euthyroid group received no thyroidectomy or treatment. The other three groups received thyroidectomies and pellets. The hypothyroid group received a placebo pellet, the DITPA group received an 80-mg DITPA-containing pellet, and the T4 group received a 5.2-mg T4 slow-release pellet for 6 wk.
Context: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct Xlinked phenotype of severe psychomotor retardation and consistently elevated T3 levels. Lack of MCT8 transport of T3 in neurons could explain the neurological phenotype.
Objective: Our objective was to determine whether the high T3 levels could also contribute to some critical features observed in these patients.
Thyroid hormone (TH) is essential for the proper development of numerous tissues, notably the brain. TH acts mostly intracellularly, which requires transport by TH transporters across the plasma membrane. Although several transporter families have been identified, only monocarboxylate transporter (MCT)8, MCT10 and organic anion-transporting polypeptide (OATP)1C1 demonstrate a high degree of specificity towards TH. Recently, the biological importance of MCT8 has been elucidated. Mutations in MCT8 are associated with elevated serum T3 levels and severe psychomotor retardation, indicating a pivotal role for MCT8 in brain development. MCT8 knockout mice lack neurological damage, but mimic TH abnormalities of MCT8 patients.
