Thyroid Hormone Transport Research Articles

Pyrethroid exposure biomarker 3-phenoxybenzoic acid (3-PBA) binds to transthyretin and is positively associated with free T3 in pregnant women

Pyrethroids constitute a large group of insecticides widely used in agriculture, indoor environments, and in vector control. Structurally, pyrethroids resemble thyroid hormones, and have been suggested to be thyroid hormone disruptors based on experimental studies. During pregnancy, even minor disturbances in maternal levels can affect fetal brain development. Therefore, we aimed to investigate whether three commonly used pyrethroids and their common metabolite, 3-PBA, were able to trigger thyroid disrupting effects on thyroid hormone production and transport, activation or deactivation of thyroid hormones, recycling of iodine, or on iodide uptake into the thyroid. Furthermore, we investigated associations between urinary 3-PBA concentrations (as biomarker of pyrethroid exposure) and serum concentrations of thyroid hormones in early pregnancy in the large prospective Odense Child Cohort (OCC).We found that the generic metabolite, 3-PBA, was capable of binding to transthyretin (TTR) at low concentrations, comparable to those reported in human cord blood. Among pregnant women in OCC, we found urinary 3-PBA concentrations to be positively associated with free triiodothyronine (fT3) serum levels. Displacement of thyroid hormones from TTR by pyrethroid exposure in early pregnancy may disturb the transplacental transport of thyroid hormones to the fetus during a very vulnerable window of development, including neural maturation. We did not find any evidence for thyroid disrupting effects in vitro for the three pyrethroids: Deltamethrin, α-cypermethrin, and etofenprox.

Neurodevelopmental delay as the initial presentation of thyroid hormone resistance syndrome

Thyroid hormone (TH) resistance syndrome is a genetic disorder usually caused by a defect in TH receptors. Moreover, transport and intracellular metabolism alterations have also been described. This case report presents a child with Allan–Herndon–Dudley syndrome characterized by a mutation on the X-linked monocarboxylate transporter 8 gene, a condition that affects the transport of THs across the cell membrane, leading to hypothyroidism in the central nervous system and hyperthyroidism in peripheral tissues, causing severe neurodevelopmental delay manifesting as generalized hypotonia from birth. The utility of monitoring thyroid functions, genetic testing, and triiodothyroacetic acid in the management is highlighted.

Assessing plasmatic transport inhibitors of thyroid hormone in mammals in the Xenopus Eleutheroembryonic Thyroid Assay (XETA).

The Xenopus Eleutheroembryonic Thyroid Assay (XETA, OECD TG 248) was established as an alternative to the Amphibian Metamorphosis Assay (AMA, OECD TG 231) for the analysis of (anti-)thyroid activity of chemicals. The XETA is a New Approach Method (NAM) since the embryonic life stages used in the assay are not yet feeding independently, which renders the assay to be considered a non-animal test under many national laws. Physiologically, the used embryos are not fully developed yet, and thus there are limitations to the XETA for detecting certain mechanisms along the hypothalamic-pituitary-thyroid (HPT) axis. However, the plasmatic transport inhibition of thyroid hormone should physiologically be detectable in the XETA but has not yet been sufficiently investigated. Here, we tested three substances that are known, amongst others, to inhibit thyroid hormone transport by competitive binding to transthyretin in mammalian studies, namely pentachlorophenol (PCP), tetrabromo bisphenol A (TBBPA), and mefenamic acid. Following the test guideline, X. laevis eleutheroembryos of Nieuwkoop-Faber stage 45 were exposed for 72h at 21°C in 6-well plates to different concentrations of the test substances. For PCP and TBBPA, the XETA showed a decrease in fluorescence intensity, which would be expected for thyroid hormone transport inhibition amongst other, similar modes of action, while for the lower potency substance mefenamic acid, a trend was visible, but no statistically significant inhibition was detected. Overall, the results indicate that in the XETA, the plasmatic transport inhibition of thyroid hormone should be detectable alongside other inhibitory modes of action on the HPT axis.

Toward a treatment for thyroid hormone transporter MCT8 deficiency - achievements and challenges.

Patients with an inactive thyroid hormone (TH) transporter MCT8 (Allan-Herndon-Dudley Syndrome, AHDS) display severe neurological impairments and motor disabilities, indicating an indispensable function of MCT8 in facilitating TH access to the human brain. Consequently, the CNS of AHDS patients appears to be in a TH deficient state, which greatly compromises proper neural development and function. Another hallmark of this disease is that patients exhibit elevated serum T3 levels, leading to a hyperthyroid situation in peripheral tissues. Several treatment strategies have been developed and evaluated in preclinical mouse models as well as in patients. Here, we discuss these different therapeutic approaches to overcome MCT8 deficiency and summarize the current achievements and challenges in improving brain maturation in the absence of MCT8.

Altered Expression of Thyroid- and Calcium Ion Channels-Related Genes in Rat Testes by Short-Term Exposure to Commercial Herbicides Paraquat or 2,4-D.

Exposure to pesticides such as paraquat and 2,4-dichlorophenoxyacetic acid (2,4-D) has been linked to harmful health effects, including alterations in male reproduction. Both herbicides are widely used in developing countries and have been associated with reproductive alterations, such as disruption of spermatogenesis and steroidogenesis. The thyroid axis and Ca2+-permeable ion channels play a key role in these processes, and their disruption can lead to reproductive issues and even infertility. This study evaluated the short-term effects of exposure to commercial herbicides based on paraquat and 2,4-D on gene expression in rat testes. At the molecular level, exposure to paraquat increased the expression of the thyroid hormone transporters monocarboxylate transporter 8 (Mct8) and organic anion-transporting polypeptide 1C1 (Oatp1c1) and the thyroid receptor alpha (TRα), suggesting a possible endocrine disruption. However, it did not alter the expression of the sperm-associated cation channels (CatSper1-2) or vanilloid receptor-related osmotically activated channel (Trpv4) related to sperm motility. In contrast, exposure to 2,4-D reduced the expression of the Mct10 transporter, Dio2 deiodinase, and CatSper1, which could affect both the availability of T3 in testicular cells and sperm quality, consistent with previous studies. However, 2,4-D did not affect the expression of CatSper2 or Trpv4. Deregulation of gene expression could explain the alterations in male reproductive processes reported by exposure to paraquat and 2,4-D. These thyroid hormone-related genes can serve as molecular biomarkers to assess endocrine disruption due to exposure to these herbicides, aiding in evaluating the health risks of pesticides.

7494 Glycerol Phenylbutyrate Treatment of Two Patients with Monocarboxylate Transporter 8 Deficiency

Abstract Disclosure: A. Zung: None. N. Sonntag: None. U. Schweizer: None. E. Banne: None. D. Braun: None. Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Currently, the two thyromimetic agents 3,5-diiodothyropropionic acid (DITPA) and triiodothyroacetic acid (TRIAC) have been evaluated in the treatment of these patients, as they both partially restore intracellular TH action independent of MCT8. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. Objective: We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. Methods: We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, serum markers of peripheral hyperthyroidism, vital signs, anthropometric measurements and neurocognitive functions by several neurodevelopment validated tests. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P32[1]L mutation. Results: NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment yielded a dose-dependent decrease in FT3 and an increase in FT4 serum levels. The patients showed an elevation in cholesterol levels in parallel with GPB dose, but sex-hormone binding protein (SHBG), another marker of peripheral hyperthyroidism was not affected. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, mainly in hyperreflexia score, slight improvement in gross motor functions and a mild progression in cognitive functions. Serum metabolites of GPB did not exceed the toxic range but elevated liver transaminases restricted the dose intensification of GPB. Conclusions: In the first report of GPB treatment in MCT8 deficiency patients we found an improvement in TH profile and body-mass index (BMI). The reduction in T3 levels could contribute to the remarkable increase in BMI-SDS, since various aspects of peripheral hyperthyroidism in MCT8 deficiency, including poor weight gain, were attributed to elevated T3. The limited effects of GPB treatment on cognitive and motor functions can derive from the advanced age of the patients at the time of the intervention. Presentation: 6/2/2024

6784 A Case of Euthyroid Hyperthyroxinemia due to Thyroid Binding Globulin Excess Syndrome

Abstract Disclosure: A.S. Iyer: None. Background: Congenital thyroid binding globulin (TBG) excess is a rare phenomenon associated with elevated serum total T3 and total T4 concentrations but normal serum concentrations of free thyroid hormones, with clinically euthyroid patients. While TBG excess can be caused by pregnancy, estrogen-secreting tumors, and estrogen therapy, congenital TBG excess follows an X-linked pattern, with hemizygous males most affected, and heterozygous females showing a spectrum of disease due to random inactivation of one X chromosome. Clinical Case: A 39-year-old Caucasian female presented as a referral from the Gastroenterology clinic due to concern for thyroid resistance syndrome. Symptoms included chronic constipation (improving with Miralax®), gradual weight gain of 8 pounds in one year, fatigue, and palpitations. She reported that her total thyroid hormone levels have always been elevated, with other thyroid labs remaining within normal limits, along with family history of similar labs noted in her two sons, father, and paternal grandmother. Upon initial encounter, TSH was 1.637 (0.430-3.550 uIU/mL), total T4 15.4 (4.8-11.7 ug/dL), total T3 231 (80-200 ng/dL), free T4 0.97 (0.70-1.25 ng/dL), free T3 3.2 (1.7-3.7 pg/mL), and albumin 4.2 (3.5-5.0 g/dL). The patient was not on oral contraceptive pills and she denied any pregnancies in the last three years. Thyroid ultrasound showed a normal-appearing homogeneous thyroid gland with a small cyst with colloid and no cervical lymphadenopathy. Initial differential diagnosis included TBG excess syndrome versus familial dysalbuminemic hyperthyroxinemia. Permission was obtained from the patient to access one of her son’s medical records from age 8-weeks old when he was also evaluated for abnormal thyroid labs. TSH was 2.144 (0.350-6.500 uIU/mL), total T4 28.2 (5.0-12.0 ug/dL), free T4 1.55 (0.8-1.8 ng/dL), and free T3 4.0 pg/mL (no reference available). Thyroid binding globulin was found to be elevated at 81 (12-26 mcg/mL) in her son and found to be elevated to 78.0 (13.5-30.9 mcg/mL) in this patient, confirming a diagnosis of TBG excess syndrome. Conclusions: TBG excess syndrome should be considered in the differential of patients with high total T3 and total T4 levels with normal levels of free T3, free T4, and TSH, especially in individuals who have a known family history and who have minimal or nonspecific symptoms. Definitive diagnosis will make further testing and treatment unnecessary. However, if these patients develop hypo- or hyperthyroidism, then use of TSH and free levels of T4 and T3 is necessary to direct management and avoid confusion. Reference: Pappa, T., and S. Refetoff. “Thyroid hormone transport proteins: Thyroxine-binding globulin, transthyretin, and albumin.” Reference Module in Neuroscience and Biobehavioral Psychology, 2017, https://doi.org/10.1016/b978-0-12-809324-5.03494-5. Presentation: 6/2/2024

Sex differences in the influence of adult-onset hypothyroidism on hippocampal progenitor survival and neuronal differentiation in mice.

The ongoing production of newborn neurons in the adult hippocampus is reported to be sensitive to perturbations of thyroid hormone signaling, in male rats and mice. Here, we examined whether the neurogenic changes evoked by adult-onset hypothyroidism exhibit sex differences, using male and female C57BL/6N mice. We assessed the impact of goitrogen-induced, adult-onset hypothyroidism on the postmitotic survival and differentiation of hippocampal progenitors in male and female mice. Adult-onset hypothyroidism evoked a significant decline in the postmitotic survival and neuronal differentiation of adult-born progenitors within the dentate gyrus hippocampal subfield of male, but not female, mice. We observed a significant decrease in the number of immature neurons within the hippocampi of adult-onset hypothyroid male mice, whereas adult-onset hypothyroidism evoked by goitrogens using the same treatment paradigms did not evoke any change in immature neuron number in female mice. Gene expression analysis within the hippocampi of euthyroid male and female mice revealed sex-dependent, differential expression of thyroid hormone receptor genes, as well as genes linked to thyroid hormone metabolism and transport. Collectively, our findings highlight sex differences in the influence of goitrogen-induced, adult-onset hypothyroidism on hippocampal neurogenesis, with male, but not female, mice exhibiting a decline in postmitotic hippocampal progenitor survival and neuronal differentiation. These findings underscore the importance of sex as a vital variable when considering the impact of thyroid hormone signaling on the adult hippocampal neurogenic niche.

A Highly Selective Fluorescent Probe for Monitoring the Thyroid Hormone Transporter Activity in Mammalian Cells.

Monocarboxylate transporter 8 (MCT8) is a trans-membrane transporter, which mediates the cellular delivery of thyroid hormones, L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3). In humans, the MCT8 protein is encoded by the SLC16A2 gene and mutations in the transporter cause a genetic neurological disorder known as Allan-Herndon-Dudley Syndrome (AHDS). MCT8 deficiency leads to impaired transport of thyroid hormones in the brain. Radiolabelled T4 and T3 or LC/MS-MS methods have been used to monitor the thyroid hormone uptake through MCT8. Herein, we developed a fluorescent based assay to monitor the thyroid hormone uptake through MCT8. A dansyl-based fluorescent probe having L-thyroxine moiety is found to be highly selective towards MCT8 in living cells. The high selectivity of the probe towards MCT8 can be attributed to the halogen bond-mediated recognition by the transporter protein. The presence of a free carboxylic acid group is essential for the specificity of the probe towards MCT8. Additionally, the selectivity of the probe for MCT8 is abolished upon esterification of the carboxylic group. Similarly, MCT8 does not recognize the probe when it contains a free amine group.

Thyroid under Attack: The Adverse Impact of Plasticizers, Pesticides, and PFASs on Thyroid Function

Endocrine-disrupting chemicals (EDCs) are synthetic or natural compounds that interfere with the endocrine system, inducing harmful effects on organisms depending on the dose and period of exposure. Numerous studies have identified concerning amounts of EDCs in environmental and human samples. The thyroid gland is essential for thyroid hormone production and controls several body functions. Several EDCs have been classified as thyroid disruptors, impairing thyroid hormone production, synthesis, metabolism, transport, and/or actions. Notably, thyroid disorders are the second most prevalent endocrine disease worldwide, with incidence increasing significantly in recent years. Some studies have correlated this rise in thyroid dysfunctions and cancers with increased exposure to EDCs. Although many EDCs are linked to thyroid dysfunction, this review focuses on the deleterious effects of plasticizers, organochlorine pesticides, and per- and poly-fluoroalkyl substances on thyroid function. These contaminants are commonly found in food, water, and everyday products. Although the impact of human exposure to these EDCs is controversial, numerous epidemiological, in vivo, and in vitro studies have indicated their harmful effects on thyroid function. Given the critical role of thyroid function and hormone production in growth, metabolism, and development, this review summarizes the consequences of exposure to thyroid disruptors for human health.

Temperature dependent cholinergic synapse induced by triphenyl phosphate and tris(1.3-dichloroisopropyl) phosphate via thyroid hormone synthesis in Cyprinus carpio

Triphenyl phosphate (TPHP) and tris(1.3-dichloroisopropyl) phosphate (TDCIPP) are emerging contaminants that pervade diverse ecosystems and impair the thyroid and neural signaling pathways. The intricate interactions between thyroid and neurodevelopmental effects mediated by TPHP and TDCIPP remain elusive. This study integrates in vivo, in vitro, and in silico approaches to elucidate these mechanisms in Cyprinus carpio at varying temperatures. It showed that TPHP and TDCIPP hindered fish growth, particularly at low temperatures, by interfering with thyroid hormone synthesis and transport processes. Both compounds have been identified as environmental hormones that mimic thyroid hormone activity and potentially inhibit acetylcholinesterase, leading to neurodevelopmental disorders characterized by brain tissue damage and disrupted cholinergic synapses, such as axon guidance and regeneration. Notably, the bioaccumulation of TPHP was 881.54 % higher than that of TDCIPP, exhibiting temperature-dependent variations with higher levels of TDCIPP at low temperatures (20.50 % and 250.84 % above optimum and high temperatures, respectively), suggesting that temperature could exacerbate the toxicity effects of OPEs. This study sheds new light on the mechanisms underlying thyroid endocrine disruption and neurodevelopmental toxicity in C. carpio. More importantly, these findings indicate that temperature affects the environmental fate and effects of TPHP and TDCIPP, which could provide an important basis for ecological environmental zoning control of emerging contaminants in the future.

Screening the ToxCast Chemical Libraries for Binding to Transthyretin.

Transthyretin (TTR) is one of the serum binding proteins responsible for transport of thyroid hormones (TH) to target tissue and for maintaining the balance of available TH. Chemical binding to TTR and subsequent displacement of TH has been identified as an end point in screening chemicals for potential disruption of the thyroid system. To address the lack of data regarding chemicals binding to TTR, we optimized an in vitro assay utilizing the fluorescent probe 8-anilino-1-napthalenesulfonic acid (ANSA) and the human protein TTR to screen over 1500 chemicals from the U.S. EPA's ToxCast ph1_v2, ph2, and e1k libraries utilizing a tiered approach. Testing of a single high concentration (target 100 μM) resulted in 888 chemicals with 20% or greater activity based on displacement of ANSA from TTR. Of these, 282 chemicals had activity of 85% or greater and were further tested in 12-point concentration-response with target concentrations ranging from 0.015 to 100 μM. An EC50 was obtained for 276 of these 301 chemicals. To date, this is the largest set of chemicals screened for binding to TTR. Utilization of this assay is a significant contribution toward expanding the suite of in vitro assays used to identify chemicals with the potential to disrupt thyroid hormone homeostasis.

Thyroid hormone transporters MCT8/OATP1C1 deficient mice exhibit increased seizure susceptibility together with an imbalanced hippocampal neurotransmission

Thyroid hormone transporters MCT8/OATP1C1 deficient mice exhibit increased seizure susceptibility together with an imbalanced hippocampal neurotransmission

Thyroid hormone transporters MCT8 and OATP1C1 are required for proper angiogenesis in the mouse CNS

Thyroid hormone transporters MCT8 and OATP1C1 are required for proper angiogenesis in the mouse CNS

Thyroid hormone transporters MCT8 and OATP1C1 exhibit cell-autonomous functions within the oligodendroglia cell lineage in the mouse CNS

Thyroid hormone transporters MCT8 and OATP1C1 exhibit cell-autonomous functions within the oligodendroglia cell lineage in the mouse CNS

Increased Thyroid Hormone Action Alleviates Hippocampal Damage by Downregulating Neuronal Type I Interferon Signaling/Necroptosis in Diabetes-Associated Cognitive Dysfunction.

Background: Thyroid dysfunction plays an important role in the pathology of diabetes-associated cognitive dysfunction (DACD). However, thyroid hormone (TH) signaling and action changes in DACD brains remain unknown. This study evaluated the alternations in TH signaling and action in the brains of DACD mice and explored the beneficial effects of levothyroxine (L-T4) treatment. Methods: KK-Ay mice, serving as a spontaneous type 2 diabetes mellitus model, underwent intragastric administration of 10 ng/g and 20 ng/g of L-T4 solution or normal saline for 8 weeks. Age-matched C57BL/6J mice were used as normal controls. Cognitive and memory functions were examined through the open field and Morris water maze tests. Hippocampal TH signaling and pathogenic status were evaluated. The potential signaling pathways involved in the neuroprotective action of L-T4 were investigated through RNA sequencing and further verified through quantitative real-time PCR (qPCR), Western blotting (WB), immunofluorescence (IF), and fluorescent multiplex immunohistochemistry (mIHC) invivo and vitro. Results: The expressions of hippocampal TH transporters (Mct8 and Oatp1c1), Dio2, and TH receptor were upregulated, whereas Dio3 as well as the TH-positive regulated genes MBP, Enpp2, and Klf9 were downregulated in DACD mice. Exogenous L-T4 partially alleviated cognitive and memory dysfunction and restored hippocampal neuronal activity by optimizing TH signaling. RNA sequencing provided insights into the role of type I interferon (IFN-I) signaling and necroptosis on the amelioration of hippocampal damage after L-T4 treatment. WB and qPCR further confirmed that the levels of key proteins for IFN-I signaling and necroptosis (p-STAT1, p-STAT2, IRF9, ZBP1, p-RIP3, and p-MLKL) were increased, but largely returned after L-T4 administration invivo and T3 treatment in vitro. IF and mIHC revealed that IRF9 and p-MLKL colocalized in neurons, but not in astrocytes or microglia, of the hippocampus in DACD mice. The diabetes mellitus group had an increased number of IRF9+ p-MLKL+ NeuN+ cells, which decreased after L-T4 treatment. The elevated IFN-I signaling-mediated necroptosis in HT22 cells was also decreased by T3. Conclusion: We demonstrated abnormal hippocampal TH signaling and action in DACD. Promoting TH action with exogenous L-T4 ameliorated hippocampal impairment through inhibiting IFN-I signaling-induced necroptosis.

Defective thyroid hormone transport to the brain leads to astroglial alterations

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.

Characterization and expression of thyroid hormone transport in HTR8/SVneo trophoblast cells under hyperinsulinemia conditions

Characterization and expression of thyroid hormone transport in HTR8/SVneo trophoblast cells under hyperinsulinemia conditions

Unmet patient needs in monocarboxylate transporter 8 (MCT8) deficiency: a review.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport. This disorder is characterized by profound neurodevelopmental delay and motor disability due to a lack of thyroid hormone in the brain, and coexisting endocrinological symptoms, due to chronic thyrotoxicosis, resulting from elevated thyroid hormone outside the central nervous system (CNS). In February 2024, we reviewed the published literature to identify relevant articles reporting on the current unmet needs of patients with MCT8 deficiency. There are several main challenges in the diagnosis and treatment of MCT8 deficiency, with decreased awareness and recognition of MCT8 deficiency among healthcare professionals (HCPs) associated with misdiagnosis and delays in diagnosis. Diagnostic delay may also be attributed to other factors, including the complex symptomology of MCT8 deficiency only becoming apparent several months after birth and pathognomonic serum triiodothyronine (T3) testing not being routinely performed. For patients with MCT8 deficiency, multidisciplinary team care is vital to optimize the support provided to patients and their caregivers. Although there are currently no approved treatments specifically for MCT8 deficiency, earlier identification and diagnosis of this disorder enables earlier access to supportive care and developing treatments focused on improving outcomes and quality of life for both patients and caregivers.

Cone photoreceptor differentiation regulated by thyroid hormone transporter MCT8 in the retinal pigment epithelium

The key role of a thyroid hormone receptor in determining the maturation and diversity of cone photoreceptors reflects a profound influence of endocrine signaling on the cells that mediate color vision. However, the route by which hormone reaches cones remains enigmatic as cones reside in the retinal photoreceptor layer, shielded by the blood-retina barrier. Using genetic approaches, we report that cone differentiation is regulated by a membrane transporter for thyroid hormone, MCT8 (SLC16A2), in the retinal pigment epithelium (RPE), which forms the outer blood-retina barrier. Mct8-deficient mice display hypothyroid-like cone gene expression and compromised electroretinogram responses. Mammalian color vision is typically facilitated by cone types that detect medium-long (M) and short (S) wavelengths of light but Mct8-deficient mice have a partial shift of M to S cone identity, resembling the phenotype of thyroid hormone receptor deficiency. RPE-specific ablation of Mct8 results in similar shifts in cone identity and hypothyroid-like gene expression whereas reexpression of MCT8 in the RPE in Mct8-deficient mice partly restores M cone identity, consistent with paracrine-like control of thyroid hormone signaling by the RPE. Our findings suggest that in addition to transport of essential solutes and homeostatic support for photoreceptors, the RPE regulates the thyroid hormone signal that promotes cone-mediated vision.