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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents



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ID: 407419.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.
Authors:Frints, Suzanna Gerarda Maria; Lenzner, Steffen; Bauters, Mareike; Jensen, Lars Riff; Van Esch, Hilde; des Portes, Vincent; Moog, Ute; Macville, Merryn Victor Erik; van Roozendaal, Kees; Schrander-Stumpel, Constance Theresia Rimbertha Maria; Tzschach, Andreas; Marynen, Peter; Fryns, Jean-Pierre; Hame, Ben; van Bokhoven, Hans; Chelly, Jamel; Beldjord, Chérif; Turner, Gillian; Gecz, Jozef; Moraine, Claude; Raynaud, Martine; Ropers, Hans Hilger; Froyen, Guy; Kuss, Andreas Walter
Language:English
Date of Publication (YYYY-MM-DD):2008-04-09
Title of Journal:European Journal of Human Genetics
Volume:16
Issue / Number:9
Start Page:1029
End Page:1037
Copyright:© 2009 European Society of Human Genetics
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Free Keywords:MCT8, Allan–Herndon–Dudley syndrome, XLMR, mutation analysis, expression, X-inactivation
Comment of the Author/Creator: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
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Clinical Genetics, University Hospital azM Maastricht, Maastricht, The Netherlands;
2.Institute for Growth and Development, GROW, Maastricht University, Maastricht, The Netherlands;
3.Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Department of Human Genetics, K.U.Leuven, Leuven, Belgium;
4.Center for Human Genetics, Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium;
5.Service de Neuropédiatrie, Hospices Civils de Lyon, Lyon, France;
6.Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;
7.INSERM Institut Cochin (IC), Département de Génétique et Pathologie Moléculaire GDPM, Equipe de Génétique et Physiopathologie du Retard Mentaux GPRM, Paris, France;
8.NSW GOLD Service, Hunter Genetics, University of Newcastle, Waratah, New South Wales, Australia;
9.Department of Genetic Medicine and Departments of Paediatrics and Molecular Biosciences, Women's and Children's Hospital and University of Adelaide, Callahan, South Australia, Australia;
10.Unité de Génétique, CHU Bretonneau, Tours, France.
Identifiers:URL:http://www.nature.com/ejhg/journal/v16/n9/abs/ejhg...
DOI:10.1038/ejhg.2008.66
ISSN:1018-4813
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