Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter

Journal of Medical Genetics (Impact Factor: 5.64). 06/2006; 43(5):457-60. DOI: 10.1136/jmg.2005.035840
Source: PubMed

ABSTRACT We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C-terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

Download full-text


Available from: Edith C H Friesema, Jul 06, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thyroid hormone (TH) has a remarkable range of actions in the development and function of the nervous system. A multigenic picture is emerging of the mechanisms that specify these diverse functions in target tissues. Distinct responses are mediated by alpha and beta isoforms of TH receptor which act as ligand-regulated transcription factors. Receptor activity can be regulated at several levels including that of uptake of TH ligand and the activation or inactivation of ligand by deiodinase enzymes in target tissues. Processes under the control of TH range from learning and anxiety-like behaviour to sensory function. At the cellular level, TH controls events as diverse as axonal outgrowth, hippocampal synaptic activity and the patterning of opsin photopigments necessary for colour vision. Overall, TH coordinates this variety of events in both central and sensory systems to promote the function of the nervous system as a complete entity.
    Molecular and Cellular Endocrinology 07/2008; 287(1-2):1-12. DOI:10.1016/j.mce.2008.03.006 · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Astrocyte cells clearly play a role in neural development, but nowadays their total action is seen as a far wider one. Recent findings consider them as stem cells, involved in the control of most facets of functional neural networks. Astrocytes play a central role in thyroid hormone metabolism in the brain, being the principal transporters of thyroxine from the blood, responsible for its conversion to 3,5,3'-triiodothyronine and hence supplying the neural tissues with the biologically active form of the hormone. Specific thyroid hormone transporters play an essential role in this regulatory system. The presence of thyroid hormone receptors has been demonstrated in cultured astrocytes. Furthermore, thyroid hormone regulates several aspects of astrocyte differentiation and maturation, including the production of extracellular matrix proteins and growth factors, and thus controls neuronal growth and neuritogenesis. Therefore, astrocytes are currently suggested as important mediators of thyroid hormone in neuronal development.
    Journal of Endocrinology 06/2006; 189(2):189-97. DOI:10.1677/joe.1.06680 · 3.59 Impact Factor
  • Source