Abstract
Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan–Herndon–Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A>T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together, these data indicate that MCT8 mutations are not common in non-AHDS MR patients yet they support that elevated serum T3 levels can be indicative for AHDS and that AHDS clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation.
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Acknowledgements
We thank Mieke Alofs (University Hospital Maastricht) and Marleen Willems (University Hospital Leuven) for their expert assistance on culturing fibroblasts, Erik van Lierop, Bertien Hollanders, Lucy Amory and Demis Tserpelis (University Hospital Maastricht) for cytogenetic and molecular X-inactivation studies. We are grateful to Bettina Moser, Melanie Wendehack and Marianne Schlicht for technical assistance in the mutation screening study. This work was supported by the Research Grant 016.066.017 of the Dutch NWO/ZonMW VENI fund, The Netherlands, Research Grant G-0229-01 of the Fund for Scientific Research-Flanders (FWO-Vlaanderen), Belgium, by the Deutsche Forschungsgemeinschaft (SFB 577) and the EURO-MRX project (part of the European ‘Quality of Life and Management of Living Resources Programme’ QLG3-CT-2002-01810).
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Frints, S., Lenzner, S., Bauters, M. et al. MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression. Eur J Hum Genet 16, 1029–1037 (2008). https://doi.org/10.1038/ejhg.2008.66
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DOI: https://doi.org/10.1038/ejhg.2008.66
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