Metabolomic Profiling of Body Fluids in Mouse Models Demonstrates that Nuclear Magnetic Resonance Is a Putative Diagnostic Tool for the Presence of Thyroid Hormone Receptor α1 Mutations
2019
Boumaza, Houda | Markossian, Suzy, S. | Busi, Baptiste | Rautureau, Gilles J.P. | Gauthier, Karine | Elena-Herrmann, Bénédicte | Flamant, Frederic | Institut des Sciences Analytiques (ISA) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | Institut de Génomique Fonctionnelle de Lyon (IGFL) ; École normale supérieure de Lyon (ENS de Lyon) ; Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Centre National de la Recherche Scientifique (CNRS) | Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) ; Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]) | Dynamique cellulaire, Immunité, Métabolisme & Cancer/Cell Dynamics, Immunity, Metabolism & Cancer (DIMAC - IAB) ; Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) ; Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre Hospitalier Universitaire [CHU Grenoble] (CHUGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA) | French National Research Agency (ANR)ANR-15-CE14-0011-04 ThyroMUT2 | ANR-15-CE14-0011,ThyroMUT2,Résistance à l'hormone thyroïdienne due à une mutation du récepteur TRa1: une maladie génétique émergente.(2015)
International audience
Show more [+] Less [-]English. Background: Resistance to thyroid hormone alpha (RTH alpha) is a rare genetic disease due to mutations in the THRA gene, which encodes thyroid hormone receptor alpha 1 (TR alpha 1). Since its first description in 2012, 46 cases of RTH alpha have been reported worldwide, corresponding to 26 different mutations of TR alpha 1. RTH alpha patients share some common symptoms with hypothyroid patients, without significant reduction in thyroid hormone level. The high variability of clinical features and the absence of reliable biochemical markers make the diagnosis of this disease difficult. Some of these mutations have been recently modeled in mice. Methods: In our study, we used four different mouse models heterozygous for frameshift mutations in the Thra gene. Two of them are very close to human mutations, while the two others have not yet been found in patients. We characterized the metabolic phenotypes of urine and plasma samples collected from these four animal models using an untargeted nuclear magnetic resonance (NMR)-based metabolomic approach. Results: Multivariate statistical analysis of the metabolomic profiles shows that biofluids of mice that carry human-like mutations can be discriminated from controls. Metabolic signatures associated with Thra mutations in urine and plasma are stable over time and clearly differ from the metabolic fingerprint of hypothyroidism in the mouse. Conclusion: Our results provide a proof-of-principle that easily accessible NMR-based metabolic fingerprints of biofluids could be used to diagnose RTH alpha in humans.
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