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Theo J. Visser - One of the best experts on this subject based on the ideXlab platform.
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Deafness and loss of cochlear hair cells in the absence of thyroid hormone transporters SLC16A2 (Mct8) and Slc16a10 (Mct10).
Scientific reports, 2018Co-Authors: David S. Sharlin, Theo J. Visser, François Verrey, Ye Liu, Rafal Olszewski, Michael Hoa, Heike Heuer, Douglas ForrestAbstract:Transmembrane proteins that mediate the cellular uptake or efflux of thyroid hormone potentially provide a key level of control over neurodevelopment. In humans, defects in one such protein, solute carrier SLC16A2 (MCT8) are associated with psychomotor retardation. Other proteins that transport the active form of thyroid hormone triiodothyronine (T3) or its precursor thyroxine (T4) have been identified in vitro but the wider significance of such transporters in vivo is unclear. The development of the auditory system requires thyroid hormone and the cochlea is a primary target tissue. We have proposed that the compartmental anatomy of the cochlea would necessitate transport mechanisms to convey blood-borne hormone to target tissues. We report hearing loss in mice with mutations in SLC16A2 and a related gene Slc16a10 (Mct10, Tat1). Deficiency of both transporters results in retarded development of the sensory epithelium similar to impairment caused by hypothyroidism, compounded with a progressive degeneration of cochlear hair cells and loss of endocochlear potential. Administration of T3 largely restores the development of the sensory epithelium and limited auditory function, indicating the T3-sensitivity of defects in the sensory epithelium. The results indicate a necessity for thyroid hormone transporters in cochlear development and function.
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Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome.
Human mutation, 2017Co-Authors: Francesca Novara, Stefan Groeneweg, Elena Freri, Margherita Estienne, Paolo Reho, Sara Matricardi, Barbara Castellotti, W. Edward Visser, Orsetta Zuffardi, Theo J. VisserAbstract:Mutations in the thyroid hormone transporter SLC16A2 (MCT8) cause the Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and peripheral thyrotoxicosis. Here, we report three newly identified AHDS patients. Previously documented mutations were identified in probands 1 (p.R271H) and 2 (p.G564R), resulting in a severe clinical phenotype. A novel mutation (p.G564E) was identified in proband 3, affecting the same Gly564 residue, but resulting in a relatively mild clinical phenotype. Functional analysis in transiently transfected COS-1 and JEG-3 cells showed a near-complete inactivation of TH transport for p.G564R, whereas considerable cell-type-dependent residual transport activity was observed for p.G564E. Both mutants showed a strong decrease in protein expression levels, but differentially affected Vmax and Km values of T3 transport. Our findings illustrate that different mutations affecting the same residue may have a differential impact on SLC16A2 transporter function, which translates into differences in severity of the clinical phenotype.
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Identification and functional characterization of zebrafish solute carrier SLC16A2 (mct8) as a thyroid hormone membrane transporter
Endocrinology, 2011Co-Authors: Francisco J. Arjona, Erik De Vrieze, Theo J. Visser, Gert Flik, Peter H.m. KlarenAbstract:Most components of the thyroid system in bony fish have been described and characterized, with the notable exception of thyroid hormone membrane transporters. We have cloned, sequenced, and expressed the zebrafish solute carrier SLC16A2 (also named monocarboxylate transporter Mct8) cDNA and established its role as a thyroid hormone transport protein. The cloned cDNA shares 56–57% homology with its mammalian orthologs. The 526-amino-acid sequence contains 12 predicted transmembrane domains. An intracellular N-terminal PEST domain, thought to be involved in proteolytic processing of the protein, is present in the zebrafish sequence. Measured at initial rate and at the body/rearing temperature of zebrafish (26 C), T3 uptake by zebrafish SLC16A2 is a saturable process with a calculated Michaelis-Menten constant of 0.8 μM T3. The rate of T3 uptake is temperature dependent and Na+ independent. Interestingly, at 26 C, zebrafish SLC16A2 does not transport T4. This implies that at a normal body temperature in zebr...
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Novel Pathogenic Mechanism Suggested by Ex Vivo Analysis of MCT8 (SLC16A2) Mutations
Human mutation, 2009Co-Authors: W. Edward Visser, Marjo S Van Der Knaap, Jurgen Jansen, Edith C. H. Friesema, Monique H. A. Kester, Edna E. Mancilla, Johan Lundgren, Roelineke J. Lunsing, Oebele F. Brouwer, Theo J. VisserAbstract:Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 arc associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501 del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3 responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501 del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations.
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Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter
The Journal of biological chemistry, 2003Co-Authors: Edith C. H. Friesema, Andrew P Halestrap, Sumita Ganguly, Amal Abdalla, Jocelyn E. Manning Fox, Theo J. VisserAbstract:Transport of thyroid hormone across the cell membrane is required for its action and metabolism. Recently, a T-type amino acid transporter was cloned which transports aromatic amino acids but not iodothyronines. This transporter belongs to the monocarboxylate transporter (MCT) family and is most homologous with MCT8 (SLC16A2). Therefore, we cloned rat MCT8 and tested it for thyroid hormone transport in Xenopus laevis oocytes. Oocytes were injected with rat MCT8 cRNA, and after 3 days immunofluorescence microscopy demonstrated expression of the protein at the plasma membrane. MCT8 cRNA induced an approximately 10-fold increase in uptake of 10 nM 125I-labeled thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and 3,3'-diiodothyronine. Because of the rapid uptake of the ligands, transport was only linear with time for
Andrew P Halestrap - One of the best experts on this subject based on the ideXlab platform.
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The SLC16 gene family – Structure, role and regulation in health and disease☆
Molecular Aspects of Medicine, 2013Co-Authors: Andrew P HalestrapAbstract:The SLC16 gene family has fourteen members. Four (SLC16A1, SLC16A3, SLC16A7, and SLC16A8) encode monocarboxylate transporters (MCT1, MCT4, MCT2, and MCT3, respectively) catalysing the proton-linked transport of monocarboxylates such as l-lactate, pyruvate and ketone bodies across the plasma membrane. SLC16A2 encodes a high affinity thyroid hormone transporter (MCT8) and SLC16A10 an aromatic amino acid transporter (TAT1). The substrates and roles of the remaining eight members are unknown. All family members are predicted to have 12 transmembrane helices (TMs) with intracellular C- and N-termini and a large intracellular loop between TMs 6 and 7. This topology has been confirmed for MCT1 and a three-dimensional structure has been modelled that suggests a plausible molecular mechanism. For correct plasma membrane expression and activity MCTs1-4, but not MCT8, require association with basigin or embigin; these are glycoproteins with a single TM and 2-3 extracellular immunoglobulin domains. SLC16 family members are involved in a wide range of metabolic pathways including energy metabolism of the brain, skeletal muscle, heart and tumour cells, gluconeogenesis, T-lymphocyte activation, bowel metabolism, spermatogenesis, pancreatic β-cell malfunction, thyroid hormone metabolism, and drug transport. MCTs 1-4 have distinct properties, tissue distribution and subcellular localisation that are appropriate for these metabolic roles. Their potential as pharmacological targets has been recognised with the discovery of potent and specific MCT1 inhibitors that act as immunosuppressant drugs by preventing proliferation of T-lymphocytes. It is suggested that the development of other drugs specifically targeting different MCT isoforms may provide a novel approach to cancer chemotherapy.
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The SLC16 gene family - structure, role and regulation in health and disease.
Molecular aspects of medicine, 2013Co-Authors: Andrew P HalestrapAbstract:The SLC16 gene family has fourteen members. Four (SLC16A1, SLC16A3, SLC16A7, and SLC16A8) encode monocarboxylate transporters (MCT1, MCT4, MCT2, and MCT3, respectively) catalysing the proton-linked transport of monocarboxylates such as l-lactate, pyruvate and ketone bodies across the plasma membrane. SLC16A2 encodes a high affinity thyroid hormone transporter (MCT8) and SLC16A10 an aromatic amino acid transporter (TAT1). The substrates and roles of the remaining eight members are unknown. All family members are predicted to have 12 transmembrane helices (TMs) with intracellular C- and N-termini and a large intracellular loop between TMs 6 and 7. This topology has been confirmed for MCT1 and a three-dimensional structure has been modelled that suggests a plausible molecular mechanism. For correct plasma membrane expression and activity MCTs1-4, but not MCT8, require association with basigin or embigin; these are glycoproteins with a single TM and 2-3 extracellular immunoglobulin domains. SLC16 family members are involved in a wide range of metabolic pathways including energy metabolism of the brain, skeletal muscle, heart and tumour cells, gluconeogenesis, T-lymphocyte activation, bowel metabolism, spermatogenesis, pancreatic β-cell malfunction, thyroid hormone metabolism, and drug transport. MCTs 1-4 have distinct properties, tissue distribution and subcellular localisation that are appropriate for these metabolic roles. Their potential as pharmacological targets has been recognised with the discovery of potent and specific MCT1 inhibitors that act as immunosuppressant drugs by preventing proliferation of T-lymphocytes. It is suggested that the development of other drugs specifically targeting different MCT isoforms may provide a novel approach to cancer chemotherapy.
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Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter
The Journal of biological chemistry, 2003Co-Authors: Edith C. H. Friesema, Andrew P Halestrap, Sumita Ganguly, Amal Abdalla, Jocelyn E. Manning Fox, Theo J. VisserAbstract:Transport of thyroid hormone across the cell membrane is required for its action and metabolism. Recently, a T-type amino acid transporter was cloned which transports aromatic amino acids but not iodothyronines. This transporter belongs to the monocarboxylate transporter (MCT) family and is most homologous with MCT8 (SLC16A2). Therefore, we cloned rat MCT8 and tested it for thyroid hormone transport in Xenopus laevis oocytes. Oocytes were injected with rat MCT8 cRNA, and after 3 days immunofluorescence microscopy demonstrated expression of the protein at the plasma membrane. MCT8 cRNA induced an approximately 10-fold increase in uptake of 10 nM 125I-labeled thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and 3,3'-diiodothyronine. Because of the rapid uptake of the ligands, transport was only linear with time for
Peter H.m. Klaren - One of the best experts on this subject based on the ideXlab platform.
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Identification and functional characterization of zebrafish solute carrier SLC16A2 (mct8) as a thyroid hormone membrane transporter
Endocrinology, 2011Co-Authors: Francisco J. Arjona, Erik De Vrieze, Theo J. Visser, Gert Flik, Peter H.m. KlarenAbstract:Most components of the thyroid system in bony fish have been described and characterized, with the notable exception of thyroid hormone membrane transporters. We have cloned, sequenced, and expressed the zebrafish solute carrier SLC16A2 (also named monocarboxylate transporter Mct8) cDNA and established its role as a thyroid hormone transport protein. The cloned cDNA shares 56–57% homology with its mammalian orthologs. The 526-amino-acid sequence contains 12 predicted transmembrane domains. An intracellular N-terminal PEST domain, thought to be involved in proteolytic processing of the protein, is present in the zebrafish sequence. Measured at initial rate and at the body/rearing temperature of zebrafish (26 C), T3 uptake by zebrafish SLC16A2 is a saturable process with a calculated Michaelis-Menten constant of 0.8 μM T3. The rate of T3 uptake is temperature dependent and Na+ independent. Interestingly, at 26 C, zebrafish SLC16A2 does not transport T4. This implies that at a normal body temperature in zebr...
Beatriz Morte - One of the best experts on this subject based on the ideXlab platform.
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Brain gene expression in systemic hypothyroidism and mouse models of MCT8 deficiency: The Mct8-Oatp1c1-Dio2 triad.
Thyroid : official journal of the American Thyroid Association, 2020Co-Authors: Beatriz Morte, Heike Heuer, Pilar Gil-ibañez, Juan BernalAbstract:Background The monocarboxylate transporter 8 (Mct8) protein is a primary T4 and T3 (TH) transporter. Mutations of the MCT8-encoding, SLC16A2 gene alters thyroid function and thyroid hormone metabolism and severely impairs neurodevelopment (Allan-Herndon-Dudley syndrome, AHDS). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is thought that Mct8 deficiency in mice is compensated by T4 transport through the Slco1c1-encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the Dio2-encoded type 2 deiodinase thus preventing brain hypothyroidism. The SLC16A2/Slco1c1 (MO) and SLC16A2/Dio2 (MD) double knockout mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, respectively, should be appropriate models of AHDS. Our goal was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double knockout (KO) mice. Methods We performed RNA sequencing using RNA from the cerebral cortex and striatum of SH mice and the double KO mice on postnatal days 21-23. Real time PCR was used to confirm RNA-Seq results in replicate biological samples. Cell type involvement was assessed from cell type enriched genes. Functional genomic differences were analyzed by functional node activity based on a probabilistic graphical model. Results Each of the three conditions gave a different pattern of gene expression, with partial overlaps. SH gave a wider and highest variation of gene expression than MD or MO. This was partially due to secondary gene responses to hypothyroidism. The set of primary transcriptional T3 targets showed more tight overlap, but quantitative gene responses indicated that the gene responses in SH were more severe than in MD or MO. Examination of cell type-enriched genes indicated cellular differences between the three conditions. Conclusion The results indicate that the neurological impairment of AHDS is too severe to be fully explained by TH deprivation only.
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Erratum: Thyroid hormone transporters—functions and clinical implications
Nature Reviews Endocrinology, 2015Co-Authors: Juan Bernal, Ana Guadaño-ferraz, Beatriz MorteAbstract:Nat. Rev. Endocrinol. 11, 406–417 (2015); doi:10.1038/nrendo.2015.66 In the original published article, reference 93 lists the incorrect article. The correct reference is Arjona, F. J. et al. Identification and functional characterization of zebrafish solute carrier SLC16A2 (Mct8) as a thyroid hormone membrane transporter.
W. Edward Visser - One of the best experts on this subject based on the ideXlab platform.
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Novel mutations in SLC16A2 associated with a less severe phenotype of MCT8 deficiency
Metabolic Brain Disease, 2019Co-Authors: Silvia Masnada, Barbara Castellotti, W. Edward Visser, Stefan Groenweg, Veronica Saletti, Luisa Chiapparini, Ettore Salsano, Davide TondutiAbstract:Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.
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Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome.
Human mutation, 2017Co-Authors: Francesca Novara, Stefan Groeneweg, Elena Freri, Margherita Estienne, Paolo Reho, Sara Matricardi, Barbara Castellotti, W. Edward Visser, Orsetta Zuffardi, Theo J. VisserAbstract:Mutations in the thyroid hormone transporter SLC16A2 (MCT8) cause the Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and peripheral thyrotoxicosis. Here, we report three newly identified AHDS patients. Previously documented mutations were identified in probands 1 (p.R271H) and 2 (p.G564R), resulting in a severe clinical phenotype. A novel mutation (p.G564E) was identified in proband 3, affecting the same Gly564 residue, but resulting in a relatively mild clinical phenotype. Functional analysis in transiently transfected COS-1 and JEG-3 cells showed a near-complete inactivation of TH transport for p.G564R, whereas considerable cell-type-dependent residual transport activity was observed for p.G564E. Both mutants showed a strong decrease in protein expression levels, but differentially affected Vmax and Km values of T3 transport. Our findings illustrate that different mutations affecting the same residue may have a differential impact on SLC16A2 transporter function, which translates into differences in severity of the clinical phenotype.
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Novel Pathogenic Mechanism Suggested by Ex Vivo Analysis of MCT8 (SLC16A2) Mutations
Human mutation, 2009Co-Authors: W. Edward Visser, Marjo S Van Der Knaap, Jurgen Jansen, Edith C. H. Friesema, Monique H. A. Kester, Edna E. Mancilla, Johan Lundgren, Roelineke J. Lunsing, Oebele F. Brouwer, Theo J. VisserAbstract:Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 arc associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501 del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3 responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501 del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations.