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    Genetics, pathophysiology and therapy of mental diseases

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    Team leaders

     

    Our team is dedicated to the study of the genetic basis of unsolved intellectual disabilities (ID) and psychiatric and neurologic diseases, including autistic syndromes and restrictive anorexia nervosa. We are developing (i) human stem cells  (IPS) derived from differentiated cells (skin) of patients; (ii) murine neuronal cell primary cultures. In these two types of cells we perform morphologic studies and search for perturbed signalization pathways possibly involved in ID syndromes. Then, in the murine models available in our laboratory, we will test the restoring potential of some pharmacological agents.  

     

    Our Program

     

    ID encompasses conditions characterized by a global IQ (intellectual quotient) lower than 70 associated with defective conceptual, practical and social capacities manifesting before the age of 18 y. Many etiological factors may be involved, including genetic and environmental elements implicated in brain development and pre- and post-natal functions. Around 40 to 50 % of moderate and severe (IQ<50) cases of mental retardation have a genetic cause  (chromosomal or gene defects). Most of the genes implicated in the occurrence of these diseases code for proteins participating in the formation or the function of synapses, and of proteins involved in the regulation of gene expression, maintenance or degradation of synaptic complexes. Several of these genes have been identified in our laboratory during the past 15 years.

    Since the introduction of NGS (next generation sequencing) technology, hundreds of additional genes have been discovered and their mutations defined in syndromic and non-syndromic ID. But their precise impact upon brain has not yet been defined.

    Our objectives are to develop cellular models consisting in (i) human induced pluripotent stem cells (iPS) derived from patients’ skin fibroblasts; (ii) primary cultures of neuronal cells. These models will be used to perform morphological and functional studies, emphasizing on cellular trafficking and signal transduction. They will be ultimately used to test the capacity of various drugs to correct the defects characterized in the preceding steps, both ex vivo and in vivo. This will be done on murine models carrying a variety of gene defects, elaborated in our lab (Ophn1, Il1rapl1, Mecp2) and in collaboration with our partners at the Institut Clinique de la Souris (ICS, Illkirch).

     

     

     

     The project is subdivided into 4 topics :

    1. Identification of novel genes involved in the determinism of Mental Diseases (K. Poirier, L. Cuisset, J. Nectoux, T. Bienvenu)
    2. Molecular and cellular patho-physiology of gene defects implicated in ID: (O. Dorseuil, T. Bienvenu, P. Billuart)
    3. Molecular basis of phenotypic variability (K. Poirier, O. Dorseuil)
    4. Therapeutic approaches (T. Bienvenu, P. Billuart)

     

     Main publications

     

    Meziane H, Khelfaoui M, Morello N, Hiba B, Calcagno E, Reibel-Foisset S, Selloum M, Chelly J, Humeau Y, Riet F, Zanni G, Herault Y, Bienvenu T, Giustetto M, Billuart P. Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability. Hum Mol Genet. 2016 25(11):2314-232

    Delepine C, Meziane H, Nectoux J, Opitz M, Smith AB, Ballatore C, Saillour Y, Bennaceur-Griscelli A, Chang Q, Williams EC, Dahan M, Duboin A, Billuart P, Herault Y, Bienvenu T. Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes. Hum Mol Genet. 2016 Jan 1;25(1):146-57.

    Lebrun N, Lebon S, Jeannet PY, Jacquemont S, Billuart P, Bienvenu T. Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A. Am J Med Genet A. 2015 Dec;167A(12):3076-81.

    Renaud J, Dumont F, Khelfaoui M, Foisset SR, Letourneur F, Bienvenu T, Khwaja O, Dorseuil O, Billuart P. Identification of intellectual disability genes showing circadian clock-dependent expression in the mouse hippocampus. Neuroscience. 2015 Nov 12;308:11-50.

    Delepine C, Nectoux J, Letourneur F, Baud V, Chelly J, Billuart P, Bienvenu T. Astrocyte Transcriptome from the Mecp2(308)-Truncated Mouse Model of Rett Syndrome. Neuromolecular Med. 2015 Dec;17(4):353-63.

    Rousseaud A, Delepine C, Nectoux J, Billuart P, Bienvenu T. Differential Expression and Regulation of Brain-Derived Neurotrophic Factor (BDNF) mRNA Isoforms in Brain Cells from Mecp2(308/y) Mouse Model. J Mol Neurosci. 2015 Aug;56(4):758-67.

    Montjean R, Aoidi R, Desbois P, Rucci J, Trichet M, Salomon R, Rendu J, Fauré  J, Lunardi J, Gacon G, Billuart P, Dorseuil O. OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells. Hum Mol Genet. 2014 24(4):994-1006 



    Team's news

     

    • Communication orale
      • « Altered microtubule-linked vesicular trafficking in MECP2-deficient astrocytes, new insight into Rett syndrome physiopathology », 1sr International meeting on Astrocytes in Paris (Octobre 1-3 2014)
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