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Relevance of Different Cellular Models in Determining the Effects of Mutations on SLC16A2/MCT8 Thyroid Hormone Transporter Function and Genotype–Phenotype Correlation

Authors

  • Yline Capri,

    1. INSERM, UMR 1103, CNRS 6293, GReD, Medical school, Clermont-Ferrand, France
    2. APHP, Genetic Department, Robert Debré University Hospital, Paris, France
    3. Université Paris Diderot, Sorbonne Paris Cité, Robert Debré University Hospital, Paris, France
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  • Edith C.H. Friesema,

    1. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
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  • Simone Kersseboom,

    1. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
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  • Renaud Touraine,

    1. Department of Clinical Chromosomal and Molecular Genetics, CHU St Etienne, France
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  • Aurélie Monnier,

    1. INSERM, UMR 1103, CNRS 6293, GReD, Medical school, Clermont-Ferrand, France
    2. Medical Cytogenetic, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
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  • Eléonore Eymard-Pierre,

    1. INSERM, UMR 1103, CNRS 6293, GReD, Medical school, Clermont-Ferrand, France
    2. Medical Cytogenetic, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
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  • Vincent Des Portes,

    1. Reference Center for Rare Intellectual Disabilities, Neuro-Paediatric Department, Debrousse Hospital, Lyon, France
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  • Giusseppe De Michele,

    1. Dipartimento di Scienze Neurologiche, Università di Napoli Federico II, Napoli, Italy
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  • Angela F. Brady,

    1. North West Thames Regional Genetics Service, Kennedy-Galton Centre, Northwick Park Hospital, Harrow, United-Kingdom
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  • Odile Boespflug-Tanguy,

    1. Université Paris Diderot, Sorbonne Paris Cité, Robert Debré University Hospital, Paris, France
    2. APHP, Reference Center for Rare diseases “Leukodystrophies”, Pediatric Neurology and Metabolic Disorders Department, Robert Debré University Hospital, Paris, France
    3. INSERM U676, Hôpital Robert Debré, Paris, France
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  • Theo J. Visser,

    1. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
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  • Catherine Vaurs-Barriere

    Corresponding author
    1. INSERM, UMR 1103, CNRS 6293, GReD, Medical school, Clermont-Ferrand, France
    2. Auvergne University, Medical School, Clermont-Ferrand, France
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  • Contract grant sponsors: Foundation of Auvergne University; French Ministry of Health (DHOS).

  • Communicated by Madhuri Hegde

ABSTRACT

SLC 16A2, the gene for the second member of the solute carrier family 16 (monocarboxylic acid transporter), located on chromosome Xq13.2, encodes a very efficient thyroid hormone transporter: monocarboxylate transporter 8, MCT8. Its loss of function is responsible in males for a continuum of psychomotor retardation ranging from severe (no motor acquisition, no speech) to mild (ability to walk with help and a few words of speech). Triiodothyronine uptake measurement in transfected cells and, more recently, patient fibroblasts, has been described to study the functional consequences of MCT8 mutations. Here, we describe three novel MCT8 mutations, including one missense variation not clearly predicted to be damaging but found in a severely affected patient. Functional studies in fibroblasts and JEG3 cells demonstrate the usefulness of both cellular models in validating the deleterious effects of a new MCT8 mutation if there is still a doubt as to its pathogenicity. Moreover, the screening of fibroblasts from a large number of patient fibroblasts and of transfected mutations has allowed us to demonstrate that JEG3 transfected cells are more relevant than fibroblasts in revealing a genotype–phenotype correlation.

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