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Nicolas CHARLET BERGUERAND
nicolas.charlet-berguerand@igbmc.fr
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Understanding The Molecular Causes Of Myotonic Dystrophies

Reference : PhD Nicolas CHARLET-BERGUERAND

Offer publication : April 5, 2016

Myotonic Dystrophies (DM) are the most common forms of adult muscular dystrophy. Patients are characterized by multiple symptoms including progressive muscular wasting, arrhythmia and cardiac conduction defects, muscle hyper-excitability (myotonia), insulin resistance and neurological troubles. These diseases are particularly disabling and there is currently no cure.
Myotonic Dystrophies are due to large expansions of non-coding RNA containing expanded CTG- or CCTG-nucleotide repeats.

These expansions are transcribed but never translated and have toxic effects at the RNA level. Indeed, expanded CUG repeats accumulate in nuclear RNA foci that sequester the muscleblind (MBNL1) protein. MBNL1 is a splicing factor and its mis-regulations in DM patients lead to specific splicing changes. For example, splicing of the chloride channel ClCN1 is modified and leads to loss of this channel, which results in myotonia in DM patients (Charlet-Berguerand et al., Mol Cell 2002). Similarly, we found that mis-regulation of the alternative splicing of BIN1 (a gene involved in muscle T-tubules formation) leads to muscle weakness (Fugier et al., Nature Medicine, 2011). Finally, we demonstrated that MBNL1 also regulates the
maturation of specific microRNA (Rau et al., Nature Structural and Molecular Biology, 2011).

Although much progress has been accomplished to understand the mechanisms of DM pathogenesis,
several points remain obscure. Notably, the molecular mechanisms underlying cardiac dysfunctions, which are the second cause of death in DM patients, are still unknown. Furthermore, there is currently no appropriate animal model to study Myotonic Dystrophies. We created novel mouse models of DM1 and of DM2 to reproduce and study pathological features of Myotonic Dystrophies, including cardiac and skeletal muscle alterations. The PhD student will be in charge of testing the muscle phenotype of our novel mouse models, this includes both in vivo (rotarod, grip test, catwalk, etc.) analyses and ex vivo testing. Also, the PhD student will be in charge of identifying novel molecular (transcriptomic and alternative splicing) alterations in these mouse models with teh help of massive parallel sequencing approaches. Finally, the PhD student will be
studying the pathological consequences of the most promising RNA alterations that he/she identified, through in vitro (gel shift, minigene, splicing assays, etc.) and in cellulo (cell culture and cell transfection/transduction, immunofluorescence, RNA FISH, etc). Hopefully, this project will help to clarify the molecular mechanisms resulting in these devatating diseases.

- WISHED SKILLS : Basic knowledge in molecular and cellular biology

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : Molecular Biology (clonage, RT-qPCR, etc.), Biochemistry (production and
purification of recombinant protein, in vitro RNA binding tests, etc), Cellular (transfection, adenoviral and lentiviral production, primary cultures of human muscle cells, etc.), Physiology (study of muscle functions in mouse models, injections and test of AAV, etc.).

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Application Deadline : Dec. 31, 2016

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