1. ¹Department of Clinical Genetics, University Hospital azM Maastricht, Maastricht, The Netherlands
2. ²Institute for Growth and Development, GROW, Maastricht University, Maastricht, The Netherlands
3. ³Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
4. ⁴Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Department of Human Genetics, K.U.Leuven, Leuven, Belgium
5. ⁵Center for Human Genetics, Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
6. ⁶Service de Neuropédiatrie, Hospices Civils de Lyon, Lyon, France
7. ⁷Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
8. ⁸INSERM Institut Cochin (IC), Département de Génétique et Pathologie Moléculaire GDPM, Equipe de Génétique et Physiopathologie du Retard Mentaux GPRM, Paris, France
9. ⁹NSW GOLD Service, Hunter Genetics, University of Newcastle, Waratah, New South Wales, Australia
10. ¹⁰Department of Genetic Medicine and Departments of Paediatrics and Molecular Biosciences, Women's and Children's Hospital and University of Adelaide, Callahan, South Australia, Australia
11. ¹¹Unité de Génétique, CHU Bretonneau, Tours, France

Correspondence: Dr SGM Frints, Department of Clinical Genetics, Maastricht University Medical Center UMC⁺, PB 5800, Maastricht 6202 AZ, The Netherlands. Tel: +31 43 3875855; Fax: +31 43 3875800; E-mail: suzanne.frints@gen.unimaas.nl; Dr AW Kuss, Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany. Tel: +49 30 84131253; Fax: +49 30 84131383; E-mail: kussa@molgen.mpg.de

¹²These authors contributed equally to this work.

Received 22 November 2007; Revised 22 February 2008; Accepted 28 February 2008; Published online 9 April 2008.

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.