Insights on the role of thyroid hormone transport in neurosensory organs and implication for the Allan–Herndon–Dudley syndrome

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Abstract

Thyroid hormones play an important role during the development and functioning of the different sensory systems. In order to exert their actions, thyroid hormones need to access their target cells through transmembrane transporter proteins, among which the monocarboxylate transporter 8 (MCT8) stands out for its pathophysiological relevance. Mutations in the gene encoding for MCT8 lead to the Allan–Herndon–Dudley syndrome (AHDS), a rare disease characterised by severe neuromotor and cognitive impairments. The impact of MCT8 deficiency in the neurosensory capacity of AHDS patients is less clear, with only a few patients displaying visual and auditory impairments. In this review we aim to gather data from different animal models regarding thyroid hormone transport and action in the different neurosensory systems that could aid to identify potential neurosensorial alterations in MCT8-deficient patients.

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Most cited references 80

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Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter.

Medhat Abdalla, Sumita Ganguly, Jocelyn Fox … (2003)

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 <4 min. MCT8 did not transport Leu, Phe, Trp, or Tyr. [125I]T4 transport was strongly inhibited by L-T4, D-T4, L-T3, D-T3, 3,3',5-triiodothyroacetic acid, N-bromoacetyl-T3, and bromosulfophthalein. T3 transport was less affected by these inhibitors. Iodothyronine uptake in uninjected oocytes was reduced by albumin, but the stimulation induced by MCT8 was markedly increased. Saturation analysis provided apparent Km values of 2-5 microM for T4, T3, and rT3. Immunohistochemistry showed high expression in liver, kidney, brain, and heart. In conclusion, we have identified MCT8 as a very active and specific thyroid hormone transporter.

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

Edith C H Friesema, Annette Grueters, Heike Biebermann … (2004)

Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2.4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.

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A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene.

Xiao-jun Liao, Alexandra Dumitrescu, Knut Brockmann … (2003)

Thyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613-amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter.

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Author and article information

Journal

Journal ID (nlm-ta): Eur Thyroid J

Journal ID (iso-abbrev): Eur Thyroid J

Journal ID (publisher-id): ETJ

Title: European Thyroid Journal

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 2235-0640

ISSN (Electronic): 2235-0802

Publication date (Electronic): 19 March 2024

Publication date (Electronic preprint): 27 February 2024

Publication date Collection: 01 April 2024

Volume: 13

Issue: 2

Electronic Location Identifier: e230241

Affiliations

[1 ]Instituto de Investigaciones Biomédicas Sols-Morreale , Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain

Author notes

Correspondence should be addressed to S Bárez-López: sbarez@ 123456iib.uam.es

^*(Á García-Aldea, M Guillén-Yunta and V Valcárcel-Hernández contributed equally to this work)

Author information

Soledad Bárez-López http://orcid.org/0000-0002-2552-0366

Article

Publisher ID: ETJ-23-0241

DOI: 10.1530/ETJ-23-0241

PMC ID: 10959056

PubMed ID: 38417253

SO-VID: a3ef89a4-bb99-4939-8ca9-b94651556ffd

License:

This work is licensed under a Creative Commons Attribution 4.0 International License.

History

Date received : 10 November 2023

Date accepted : 27 February 2024

Funding

Funded by: Ministerio de Universidades, doi http://dx.doi.org/10.13039/501100023561;

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Insights on the role of thyroid hormone transport in neurosensory organs and implication for the Allan–Herndon–Dudley syndrome

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