Mutations of the Thyroid Hormone Transporter MCT8 Cause Prenatal Brain Damage and Persistent Hypomyelination

López-Espíndola, Daniela; Morales-Bastos, Carmen; Grijota-Martínez, Carmen; Liao, Xiao-Hui; Lev, Dorit; Sugo, Ella; Verge, Charles F.; Refetoff, Samuel; Bernal, Juan; Guadaño-Ferraz, Ana

doi:10.1210/jc.2014-2162

Cited by 132 publications

(157 citation statements)

References 18 publications

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“…Based on a post-mortem study on a 30th gestational week MCT8-deficient foetus and an 11-yearold AHDS patient, it was suggested that an impaired TH supply to neural cells is the likely cause of the severe insult to the developing brain. Moreover, histological and biochemical abnormalities were compatible with a large number of clinical symptoms related to impaired cerebellar function (Lopez-Espindola et al 2014).…”

Section: Introductionmentioning

confidence: 73%

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

Delbaere

Vancamp

Herck

et al. 2017

Journal of Endocrinology

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Inactivating mutations in the human SLC16A2 gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in the Allan-Herndon-Dudley syndrome accompanied by severe locomotor deficits. The underlying mechanisms of the associated cerebellar maldevelopment were studied using the chicken as a model. Electroporation of an MCT8-RNAi vector into the cerebellar anlage of a 3-dayold embryo allowed knockdown of MCT8 in Purkinje cell precursors. This resulted in the downregulation of the thyroid hormone-responsive gene RORα and the Purkinje cell-specific differentiation marker LHX1/5 at day 6. MCT8 knockdown also results in a smaller and less complex dendritic tree at day 18 suggesting a pivotal role of MCT8 for cell-autonomous Purkinje cell maturation. Early administration of the thyroid hormone analogue 3,5,3′-triiodothyroacetic acid partially rescued early Purkinje cell differentiation. MCT8-deficient Purkinje cells also induced non-autonomous effects as they led to a reduced granule cell precursor proliferation, a thinner external germinal layer and a loss of PAX6 expression. By contrast, at day 18, the external germinal layer thickness was increased, with an increase in presence of Axonin-1-positive post-mitotic granule cells in the initial stage of radial migration. The concomitant accumulation of presumptive migrating granule cells in the molecular layer, suggests that inward radial migration to the internal granular layer is stalled. In conclusion, early MCT8 deficiency in Purkinje cells results in both cell-autonomous and non-autonomous effects on cerebellar development and indicates that MCT8 expression is essential from very early stages of development, providing a novel insight into the ontogenesis of the Allan-HerndonDudley syndrome.

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Section: Introductionmentioning

confidence: 73%

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

Delbaere

Vancamp

Herck

et al. 2017

Journal of Endocrinology

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“…It is important to appreciate that the absence of overt behavioral abnormalities at birth does not imply the absence of underlying brain structural or functional abnormalities. For example, an examination of post-mortem brains from a 30 week old fetus as well as a child with a mutation in the MCT8 transporter (which leads to TH deficiency selectively in the brain) showed that brain damage is already present during the fetal period, while behavioral alterations may become apparent only at later stages of life (Lopez-Espindola et al, 2014). …”

Section: Influence Of Ths On Brain and Cognitive Developmentmentioning

confidence: 99%

Influence of maternal thyroid hormones during gestation on fetal brain development

et al. 2017

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Thyroid hormones (TH) play an obligatory role in many fundamental processes underlying brain development and maturation. The developing embryo/fetus is dependent on maternal supply of TH. The fetal thyroid gland does not commence THs synthesis until mid gestation, and the adverse consequences of severe maternal TH deficiency on offspring neurodevelopment are well established. Recent evidence suggests that even more moderate forms of maternal thyroid dysfunction, particularly during early gestation, may have a long-lasting influence on child cognitive development and risk of neurodevelopmental disorders. Moreover, these observed alterations appear to be largely irreversible after birth. It is, therefore, important to gain a better understanding of the role of maternal thyroid dysfunction on offspring neurodevelopment in terms of the nature, magnitude, time-specificity, and context-specificity of its effects. With respect to the issue of context specificity, it is possible that maternal stress and stress-related biological processes during pregnancy may modulate maternal thyroid function. The possibility of an interaction between the thyroid and stress systems in the context of fetal brain development has, however, not been addressed to date. We begin this review with a brief overview of TH biology during pregnancy and a summary of the literature on its effect on the developing brain. Next, we consider and discuss whether and how processes related to maternal stress and stress biology may interact with and modify the effects of maternal thyroid function on offspring brain development. We synthesize several research areas and identify important knowledge gaps that may warrant further study. The scientific and public health relevance of this review relates to achieving a better understanding of the timing, mechanisms and contexts of thyroid programming of brain development, with implications for early identification of risk, primary prevention and intervention.

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“…This was shown in a recent study of human brains from a fetus and child with AHDS. Both brains had anatomic and structural changes consistent with severe abnormalities of development concurrent with greatly diminished cerebral T3 levels (Lopez-Espindola et al, 2014). Also, the relationship of AHDS to a deficiency of T3 transport has been solidified by studies showing that human fetal and neonatal brain from patients with AHDS look remarkably similar to brain from humans with severe hypothyroidism (Gagliardi et al, 2015; J.…”

Section: Thyroid Hormone Transportersmentioning

confidence: 99%

New insights into thyroid hormone action

Mendoza

Hollenberg

2017

Pharmacology & Therapeutics

207

136

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Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is exquisitely modulated to maintain nearly constant TH (T4 and T3) concentrations in circulation. However peripheral tissues and the CNS control the intracellular availability of TH, suggesting that circulating concentrations of TH are not fully representative of what each cell type sees. Indeed, recent work in the field has identified that TH transporters, deiodinases and thyroid hormone receptor coregulators can strongly control tissue-specific sensitivity to a set amount of TH. Furthermore, the mechanism by which the thyroid hormone receptors regulate target gene expression can vary by gene, tissue and cellular context. This review will highlight novel insights into the machinery that controls the cellular response to TH, which include unique signaling cascades. These findings shed new light into the pathophysiology of human diseases caused by abnormal TH signaling.

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Mutations of the Thyroid Hormone Transporter MCT8 Cause Prenatal Brain Damage and Persistent Hypomyelination

Cited by 132 publications

References 18 publications

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

Influence of maternal thyroid hormones during gestation on fetal brain development

New insights into thyroid hormone action

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