Thyroid Hormone Transporter Deficiency in Mice Impacts Multiple Stages of GABAergic Interneuron Development.

Cortical interneuron neurogenesis is strictly regulated and depends on the presence of thyroid hormone (TH). In particular, inhibitory interneurons expressing the calcium binding protein Parvalbumin are highly sensitive toward developmental hypothyroidism. Reduced numbers of Parvalbumin-positive interneurons are observed in mice due to the combined absence of the TH transporters Mct8 and Oatp1c1. To unravel if cortical Parvalbumin-positive interneurons depend on cell-autonomous action of Mct8/Oatp1c1, we compared Mct8/Oatp1c1 double knockout (dko) mice to conditional knockouts with abolished TH transporter expression in progenitors of Parvalbumin-positive interneurons. These conditional knockouts exhibited a transient delay in the appearance of Parvalbumin-positive interneurons in the early postnatal somatosensory cortex while cell numbers remained permanently reduced in Mct8/Oatp1c1 dko mice. Using fluorescence in situ hybridization on E12.5 embryonic brains, we detected reduced expression of sonic hedgehog signaling components in Mct8/Oatp1c1 dko embryos only. Moreover, we revealed spatially distinct expression patterns of both TH transporters at brain barriers at E12.5 by immunofluorescence. At later developmental stages, we uncovered a sequential expression of first Oatp1c1 in individual interneurons and then Mct8 in Parvalbumin-positive subtypes. Together, our results point to multiple cell-autonomous and noncell-autonomous mechanisms that depend on proper TH transport during cortical interneuron development.

Triac Treatment Prevents Neurodevelopmental and Locomotor Impairments in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice.

Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3'-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.

Role of thyroid hormones in normal and abnormal central nervous system myelination in humans and rodents.

Thyroid hormones (THs) are instrumental in promoting the molecular mechanisms which underlie the complex nature of neural development and function within the central nervous system (CNS) in vertebrates. The key neurodevelopmental process of myelination is conserved between humans and rodents, of which both experience peak fetal TH concentrations concomitant with onset of myelination. The importance of supplying adequate levels of THs to the myelin producing cells, the oligodendrocytes, for promoting their maturation is crucial for proper neural function. In this review we examine the key TH distributor and transport proteins, including transthyretin (TTR) and monocarboxylate transporter 8 (MCT8), essential for supporting proper oligodendrocyte and myelin health; and discuss disorders with impaired TH signalling in relation to abnormal CNS myelination in humans and rodents. Furthermore, we explore the importance of using novel TH analogues in the treatment of myelination disorders associated with abnormal TH signalling.

A novel frameshift mutation in Allan-Herndon-Dudley syndrome.

Allan-Herndon-Dudley syndrome (AHDS) is a very rare, X-linked psychomotor disability syndrome with delayed myelination, almost exclusively affecting boys. We present a case of a 4-year-old boy with AHDS who was found cyanotic, with intermittent vomiting and paroxysmal convulsions about 4 h after his parents went out, and was then taken to the hospital, where he eventually died the next day. The autopsy revealed foreign bodies in the tiny bronchi and alveoli of the deceased, congestion, and punctate hemorrhage in multiple organs, consistent with the diagnosis of asphyxia. Compared with a normally developing 4-year-old boy, the deceased showed cerebral atrophy and cerebral edema, and Luxol Fast Blue (LFB) stain indicated delayed cerebellar, hippocampal, and basal ganglia development and myelination. A novel frameshift mutation c.584delG in the SLC16A2 gene was detected. Family lineage investigation showed that the mutation was also detected in the deceased's 8-year-old brother and biological mother. The present work enriches the profile mutations in SLC16A2 related to AHDS and emphasizes the importance of autopsy and postmortem genetic analysis in such cases.

A novel variant in SLC16A2 associated with typical Allan-Herndon-Dudley syndrome: a case report.

BACKGROUND: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked recessive neurodegenerative disorder caused by mutations in the SLC16A2 gene that encodes thyroid hormone transporter. AHDS has been rarely reported in China. CASE PRESENTATION: This study reported a novel splicing mutation in the SLC16A2 gene in an 18-month-old male patient with AHDS. The patient was born to non-consanguineous, healthy parents of Chinese origin. He passed new-born screening for hypothyroidism, but failed to reach developmental milestones. He presented with hypotonia, severe mental retardation, dysarthria and ataxia. Genetic analysis identified a novel splicing mutation, NM_006517.4: c.431-2 A > G, in the SLC16A2 gene inherited from his mother. The patient received Triac treatment, (triiodothyroacetic acid), a thyroid hormone analogue for 3 months. Triac treatment effectively reduced serum TSH concentrations and normalized serum T3 concentrations in the patient. CONCLUSIONS: This study reported the first case of AHDS treated by Triac in China. And the study expanded the mutational spectrum of the SLC16A2 gene in AHDS patients.

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice.

Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3',5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency.

First female with Allan-Herndon-Dudley syndrome and partial deletion of X-inactivation center.

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion.

Functional analysis of monocarboxylate transporter 8 mutations in Japanese Allan-Herndon-Dudley syndrome patients.

Monocarboxylate transporter 8 (MCT8) facilitates T3 uptake into cells. Mutations in MCT8 lead to Allan-Herndon-Dudley syndrome (AHDS), which is characterized by severe psychomotor retardation and abnormal thyroid hormone profile. Nine uncharacterized MCT8 mutations in Japanese patients with severe neurocognitive impairment and elevated serum T3 levels were studied regarding the transport of T3. Human MCT8 (hMCT8) function was studied in wild-type (WT) or mutant hMCT8-transfected human placental choriocarcinoma cells (JEG3) by visualizing the locations of the proteins in the cells, detecting specific proteins, and measuring T3 uptake. We identified 6 missense (p.Arg445Ser, p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, and p.Gly312Arg), 2 frameshift (p.Arg355Profs*64 and p.Tyr550Serfs*17), and 1 deletion (p.Pro561del) mutation(s) in the hMCT8 gene. All patients exhibited clinical characteristics of AHDS with high free T3, low-normal free T4, and normal-elevated TSH levels. All tested mutants were expressed at the protein level, except p.Arg355Profs*64 and p.Tyr550Serfs*17, which were truncated, and were inactive in T3 uptake, excluding p.Arg445Ser and p.Pro561del mutants, compared with WT-hMCT8. Immunocytochemistry revealed plasma membrane localization of p.Arg445Ser and p.Pro561del mutants similar with WT-hMCT8. The other mutants failed to localize in significant amount(s) in the plasma membrane and instead localized in the cytoplasm. These data indicate that p.Arg445Ser and p.Pro561del mutants preserve residual function, whereas p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, p.Gly312Arg, p.Arg355Profs*64, and p.Tyr550Serfs*17 mutants lack function. These findings suggest that the mutations in MCT8 cause loss of function by reducing protein expression, impairing trafficking of protein to plasma membrane, and disrupting substrate channel.

Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome.

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.

Hypomyelinating leukodystrophies - a molecular insight into the white matter pathology.

Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

Allan-Herndon-Dudley syndrome with unusual profound sensorineural hearing loss.

The Allan-Herndon-Dudley syndrome is caused by mutations in the thyroid hormone transporter, Monocarboxylate transporter 8 (MCT8). It is characterized by profound intellectual disability and abnormal thyroid function. We report on a patient with Allan-Herndon-Dudley syndrome (AHDS) with profound sensorineural hearing loss which is not usually a feature of AHDS and which may have been due to a coexisting nonsense mutation in Microphthalmia-associated transcription factor (MITF).

Identification of Human TRIAC Transmembrane Transporters.

Background: 3,5,3'-Triiodothyroacetic acid (TRIAC) is a T3-receptor agonist pharmacologically used in patients to mitigate T3 resistance. It is additionally explored to treat some symptoms of patients with inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8, SLC16A2). MCT8 is expressed along the blood-brain barrier, on neurons, astrocytes, and oligodendrocytes. Hence, pathogenic variants in MCT8 limit the access of TH into and their functions within the brain. TRIAC was shown to enter the brain independently of MCT8 and to modulate expression of TH-dependent genes. The aim of the study was to identify transporters that facilitate TRIAC uptake into cells. Methods: We performed a whole-genome RNAi screen in HepG2 cells stably expressing a T3-receptor-dependent luciferase reporter gene. Validation of hits from the primary and confirmatory secondary screen involved a counter screen with siRNAs and compared the cellular response to TRIAC to the effect of T3, in order to exclude siRNAs targeting the gene expression machinery. MDCK1 cells were stably transfected with cDNA encoding C-terminally myc-tagged versions of the identified TRIAC-preferring transporters. Several individual clones were selected after immunocytochemical characterization for biochemical characterization of their 125I-TRIAC transport activities. Results: We identified SLC22A9 and SLC29A2 as transporters mediating cellular uptake of TRIAC. SLC22A9 encodes the organic anion transporter 7 (OAT7), a sodium-independent organic anion transporter expressed in the plasma membrane in brain, pituitary, liver, and other organs. Competition with the SLC22A9/OAT7 substrate estrone-3-sulfate reduced 125I-TRIAC uptake. SLC29A2 encodes the equilibrative nucleoside transporter 2 (ENT2), which is ubiquitously expressed, including pituitary and brain. Coincubation with the SLC29A2/ENT2 inhibitor nitrobenzyl-6-thioinosine reduced 125I-TRIAC uptake. Moreover, ABCD1, an ATP-dependent peroxisomal pump, was identified as a 125I-TRIAC exporter in transfected MDCK1 cells. Conclusions: Knowledge of TRIAC transporter expression patterns, also during brain development, may thus in the future help to interpret observations on TRIAC effects, as well as understand why TRIAC may not show a desirable effect on cells or organs not expressing appropriate transporters. The identification of ABCD1 highlights the sensitivity of our established screening assay, but it may not hold significant relevance for patients undergoing TRIAC treatment.

Impact of Early Intervention with Triiodothyroacetic Acid on Peripheral and Neurodevelopmental Findings in a Boy with MCT8 Deficiency

Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disorder characterized by peripheral thyrotoxicosis and severe cognitive and motor disability due to cerebral hypothyroidism. 3,3',5-triiodothyroacetic acid (Triac) was shown to improve peripheral thyrotoxicosis but data on neurodevelopmental outcome are scarce. We present a case of MCT8 deficiency and the experience with Triac focusing on change in neurodevelopmental and peripheral features. A five-month-old boy was referred because of feeding difficulty, central hypotonia and global developmental delay. Despite six months of physiotherapy, physical developmental milestones did not improve, and distal muscle tone was increased. A hemizygous pathogenic variant in SLC16A2 was found and MCT8 deficiency was confirmed at 19-months. Thyroid stimulating hormone was 2.83 mIU/mL, free thyroxine 6.24 pmol/L (N=12-22) and free triiodothyronine (FT3) 15.65pmol/L (N=3.1-6.8). He had tachycardia, blood pressure and transaminases were elevated. Triac was started at 21-months. Two weeks after treatment, FT3 dramatically decreased, steady normal serum FT3 was achieved at 28-months. Assessment of neurodevelopmental milestones and signs of hyperthyroidism were evaluated at baseline, 6 months and 12 months after treatment. Signs of hyperthyroidism were improved by 6 months. Developmental composite scores of Bayley Scales of Infant Developmental 3rd Edition remained the same but important developmental milestones (head control, recognition of caregiver, response to his name) were attained, regression in the attained milestones were not observed. Initial dose, management protocol for Triac and research into its efficacy on neurodevelopmental signs in MCT8 deficiency are progressing. This case presents evidence that Triac may resolve peripheral thyrotoxicosis successfully and may slow neurodevelopmental regression, while some developmental milestones were achieved after one year of treatment.

Phenylbutyrate Treatment in a Boy with MCT8 Deficiency: Improvement of Thyroid Function Tests and Possible Livertoxicity.

CONTEXT: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations. OBJECTIVE: The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G > T (p.V235L). RESULTS: During a treatment period of 13 months, PB led to a significant decrease of elevated TSH and T3 serum concentrations, while fT4 increased. Weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate (PAA) in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity. CONCLUSION: In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies towards body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation.

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.

Late diagnosis of the X-linked MCT8 deficiency (Allan-Herndon-Dudley syndrome) in a teenage girl with primary ovarian insufficiency.

OBJECTIVES: To report an unusual case of MCT8 deficiency (Allan-Herndon-Dudley syndrome), an X-linked condition caused by pathogenic variants in the SLC16A2 gene. Defective transport of thyroid hormones (THs) in this condition leads to severe neurodevelopmental impairment in males, while heterozygous females are usually asymptomatic or have mild TH abnormalities. CASE PRESENTATION: A girl with profound developmental delay, epilepsy, primary amenorrhea, elevated T3, low T4 and free T4 levels was diagnosed with MCT8-deficiency at age 17 years, during evaluation for primary ovarian insufficiency (POI). Cytogenetic analysis demonstrated balanced t(X;16)(q13.2;q12.1) translocation with a breakpoint disrupting SLC16A2. X-chromosome inactivation studies revealed a skewed inactivation of the normal X chromosome. CONCLUSIONS: MCT8-deficiency can manifest clinically and phenotypically in women with SLC16A2 aberrations when nonrandom X inactivation occurs, while lack of X chromosome integrity due to translocation can cause POI.

Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan-Herndon-Dudley Syndrome.

BACKGROUND: Deficiencies in the thyroid hormone transporter monocarboxylate 8 (MCT8) due to pathogenic variants in the SLC16A2 gene (OMIM 300095) result in a complex phenotype with main endocrine and neurologic symptoms. This rare disorder, named Allan-Herndon-Dudley syndrome (AHDS) (OMIM 300523), is inherited in an X-linked trait. One of the prominent features of AHDS is the presence of movement disorders (MD), which are complex and carry a significant burden of the disease. CASES: Patient 1: male with hypotonia since birth, developmental delay, dystonic posturing at 4 months and at 15 months, and startle reaction developed with sensory stimuli. Patient 2: male, at 2 months, shows hypotonia and developmental delay, paroxysmal episodes triggered by a stimulus with sudden blush, tonic asymmetric posture, and no epileptiform activity. At 10 months, generalized dystonic posturing. Patient 3: typical neurodevelopmental milestones until 6 months; at 24 months, dystonia, startle reaction, and upper motoneuron signs. CONCLUSIONS: We aim to describe our patients diagnosed with AHDS, focusing on MD phenomenology and strengthening the phenotype-genotype correlations for this rare condition.

Regulators of thyroid hormone availability and action in embryonic chicken brain development.

Thyroid hormones (THs) are crucial elements in vertebrate brain development. They exert their action mainly through binding of 3,5,3'-triiodothyronine (T3) to nuclear receptors that directly influence the expression of TH-regulated genes. Intracellular TH action is therefore dependent on both the availability of T3 and its receptors. TH uptake in cells is regulated by specific TH transporters and local activation and inactivation is regulated by deiodinases. This review provides an overview of the general expression pattern of TH transporters, deiodinases and receptors during embryonic chicken brain development and compares it to the situation in mammals. It is clear that THs and their regulators are present in the embryonic brain from the early stages of development, long before the onset of embryonic thyroid gland functioning. The mechanism of TH uptake across the brain barriers during development is only partly understood. At the developing blood-brain-barrier expression of the TH-activating type 2 deiodinase is closely associated with the blood vessels, but contrary to the situation in (adult) mammals no expression of MCT8 or OATP1C1 TH transporters is found at that level in the developing chicken. At the blood-cerebrospinal fluid-barrier co-expression of the TH-inactivating type 3 deiodinase and MCT8 and OATP1C1 is found in birds and mammals. These comparative data show overlapping patterns, pointing to general mechanisms, but also indicate specific interspecies differences that may help to understand species-specific responses to regulator gene knockout/mutation.

Generation of iPSC lines with SLC16A2:G401R or SLC16A2 knock out.

The X-linked Allan-Herndon-Dudley syndrome (AHDS) is characterized by severely impaired psychomotor development and is caused by mutations in the SLC16A2 gene encoding the thyroid hormone transporter MCT8 (monocarboxylate transporter 8). By targeting exon 3 of SLC16A2 using CRISPR/Cas9 with single-stranded oligodeoxynucleotides as homology-directed repair templates, we introduced the AHDS patient missense variant G401R and a novel knock-out deletion variant (F400Sfs*17) into the male healthy donor hiPSC line BIHi001-B. We successfully generated cerebral organoids from these genome-edited lines, demonstrating the utility of the novel lines for modelling the effects of MCT8-deficency on human neurodevelopment.

Corrigendum: In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity.

[This corrects the article DOI: 10.3389/fendo.2023.1157685.].