DS0405 - Génétique et génomique: relation génotype-phénotype, interactions génome-environnement, épigénétique

Resistance to thyroid hormone due to TRa1 mutation: an emerging genetic disease. – ThyroMUT2

Submission summary

This program is dedicated to a new type of resistance to thyroid hormone (RTHa), which is due to a mutation of the TRa1 receptor, encoded by the THRA gene .This rare genetic disease, for which the clinical features are surprisingly variable, was discovered in 2012. The patients are heterozygous and carry mutations transforming the receptor into a dominant negative. The pleiotropic consequences of the mutation usually include impaired growth and ossification, mental retardation and constipation. However TH levels in serum remain within the normal range. As most clinicians are not aware of the disease, and since the symptoms are not highly specific, it is likely that the number of patients is highly underestimated, despite its debilitating consequences.
We gathered 4 partners with complementary skills, ranging from biochemistry, nuclear magnetic resonance analysis and mouse genetics, to clinical studies to shed new light on all aspects of this disease: diagnosis, etiology and therapy. Our first goal is to generate knowledge to facilitate RTHa diagnosis. For this purpose, our program will use available animal and cellular models of RTHa, and generate new ones. The molecular basis underlying the phenotype variability associated with the different THRA mutations will be deciphered. Finally we will provide proof of principle for treatment. To reach these objectives we have divided the program into the following tasks.

Task1 is dedicated to the dissemination of RTHa knowledge and the discovery of new patients. An international network of hospitals, in France and China, will help to identify putative RTHa patients for which DNA sequencing of THRA will be performed.
Task 2 goal is to generate new mouse models. Although we already possess a large collection of mouse strains with THRA mutations, we will generate other “tailor-made’” models, using the CRISPR/Cas9 editing method. We will copy mutations found in the ligand binding or DNA binding domain of TRa1, present in patients or only in anonymous exome databases.
In Task 3, we will use the full collection of mouse models to look for a discriminant metabonomic signature of RTHa in urine or serum. This approach will then transpose to patient samples in order to provide new diagnostic tools.
Task 4 is conceived to develop a pipeline for a full structural and functional characterization of THRA mutations. This will include biochemical studies of the mutant receptors in vitro, transcriptional analyses of cells co-expressing mutant and wild-type TR and phenotyping mice carrying these mutations. Our preliminary data encourages us to focus our analysis on 2 cell types, of high clinical relevance: GABAergic neurons and macrophages.
Task 5 intends to promote further clinical exploration in patients and to provide a proof of principle for therapeutic intervention. We will test in our mouse and cellular models the possibility of using approved drugs, which have the property of inhibiting the activity of the co-repressors that mutant TRa1 recruits in a TH-independent manner on the chromatin. Such compounds should thus antagonize the detrimental effect exerted by the mutant TRa1 receptor and provide some improvement of the RTHa symptoms.

Project coordination

Frédéric FLAMANT (Institut de Génomique Fonctionnelle de Lyon)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

ISA CNRS Institut des Sciences Analytiques
IGFL Institut de Génomique Fonctionnelle de Lyon
INSERM U1083 Laboratoire Biologie Neurovasculaire et Mitochondriale Intégrée INSERM Unité U1083
INSERM U1054 Centre de Biochimie Structurale de Montpellier

Help of the ANR 546,832 euros
Beginning and duration of the scientific project: September 2015 - 48 Months

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