Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation

Friesema, Edith C. H.; Grueters, Annette; Biebermann, Heike; Krude, Heiko; Moers, Arpad von; Reeser, Maarten; Barrett, Timothy; Mancilla, Edna E.; Svensson, Johan; Kester, Maartje I.; Kuiper, George G. J. M.; Balkassmi, Sahila; Uitterlinden, André G.; Koehrle, Josef; Rodien, Patrice; Halestrap, Andrew P.; Visser, Theo J.

doi:10.1016/s0140-6736(04)17226-7

Cited by 641 publications

(431 citation statements)

References 6 publications

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“…Several types of patients with genetic defects in thyroid hormone signaling have been identified during the past decade, including those with mutations in thyroid hormone transporters (38) and receptors (14,39). In mice and humans, these defects often result in strongly impaired brain function.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Mittag¹,

Lyons²,

Sällström³

et al. 2012

J. Clin. Invest.

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Thyroid hormone is well known for its profound direct effects on cardiovascular function and metabolism. Recent evidence, however, suggests that the hormone also regulates these systems indirectly through the central nervous system. While some of the molecular mechanisms underlying the hormone's central control of metabolism have been identified, its actions in the central cardiovascular control have remained enigmatic. Here, we describe a previously unknown population of parvalbuminergic neurons in the anterior hypothalamus that requires thyroid hormone receptor signaling for proper development. Specific stereotaxic ablation of these cells in the mouse resulted in hypertension and temperature-dependent tachycardia, indicating a role in the central autonomic control of blood pressure and heart rate. Moreover, the neurons exhibited intrinsic temperature sensitivity in patch-clamping experiments, providing a new connection between cardiovascular function and core temperature. Thus, the data identify what we believe to be a novel hypothalamic cell population potentially important for understanding hypertension and indicate developmental hypothyroidism as an epigenetic risk factor for cardiovascular disorders. Furthermore, the findings may be beneficial for treatment of the recently identified patients that have a mutation in thyroid hormone receptor α1. IntroductionThyroid hormone is a well-known regulator of cardiovascular function and metabolic rate (1, 2). Hyperthyroid patients display increased metabolic rate and weight loss, despite increased food intake, as well as a profound tachycardia (2). Conversely, hypothyroid patients often suffer from weight gain and bradycardia (3). While most of the cardiovascular and metabolic effects of thyroid hormone have been attributed to direct actions in the corresponding peripheral tissues, such as heart (4) or skeletal muscle and fat (5, 6), recent studies have demonstrated that the hormone modulates these processes also through the brain (7): injections of thyroid hormone into different brain regions stimulate energy expenditure (8), and thyroid hormone signaling is required to establish the metabolic set point during embryonal development (9, 10).Similarly, thyroid hormone signaling is needed for the central modulation of heart rate. Mice that are heterozygous for a point mutation in thyroid hormone receptor α1 (Thra1 +/m ), which reduces the affinity to the ligand 10 fold (11), were unable to mount a correct cardiovascular response to stress, activity, or changes in environmental temperature due to a defective autonomous nervous system (12). While progress has been made in unraveling the molecular mechanisms of action of thyroid hormone in the central metabolic control and the identification of the underlying neuroanatomical areas (13), little is known about the anatomical substrates that mediate the effects of thyroid hormone on cardiovascular function.Here, we show that Thra1 +/m mice exhibit fewer parvalbuminergic neurons in a previously unknown population in the ant...

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Section: Discussionmentioning

confidence: 99%

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Mittag¹,

Lyons²,

Sällström³

et al. 2012

J. Clin. Invest.

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“…In 2004, loss‐of‐function mutations within the SLC16A2 gene, located on the X chromosome, encoding for the thyroid hormone transporter MCT8, have been identified as the monogenetic cause of AHDS 75, 76. Thyroid hormones play essential roles in growth and development of various tissues, especially the brain, and rely on cellular uptake to fulfill their physiological functions 77.…”

Section: Ophthalmological Diseasesmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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“…Solute carriers known to transport thyroid hormones include monocarboxylate transporters (MCTs), Na + /taurocholate co-transporting polypeptide, organic anion transporters (OATs), amino acid transporters (e.g., L-type amino acid transporters), and organic anion transporting polypeptides (OATPs) (102)(103)(104)(105)(106). The importance of thyroid hormone transporters is illustrated by the fact that mutations in human MCT8 cause psychomotor retardation and altered iodothyronine levels (107,108). With the exception of OATP1C1 (T 4 and 3,3¢,5¢-triiodothyronine [rT 3 ] transport only), most thyroid hormone transporters transport both T 4 and T 3 .…”

Section: [B3] Sources Of Tissue T 3 and Tr Saturationmentioning

confidence: 99%

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Bianco

Anderson

Forrest

et al. 2014

Thyroid

174

106

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Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation

Cited by 641 publications

References 6 publications

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

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