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Alternate translational initiation and amelioration of phenotype in the DMD gene

Research Scholar

Nicolas Wein, Children's Hospital - Pediatrics (France)
Michael T. Howard, Co-Researcher
Daniel Schoenberg, Co-Researcher
Baskar Bakthavachalu, Co-Researcher
Adeline Vulin, Co-Researcher
Andrew Findlay, Co-Researcher
Baijayanta Maiti, Co-Researcher
Kevin M. Flanigan, Faculty Mentor

Biography

Nicolas Wein built his career by starting a PhD in Nicolas Levy's laboratory (France) working on dysferlinopathies, a muscular dystrophy. He developed tools for diagnosis, acquired a broad experience in cell biology and developed specific therapeutics tools. To further broaden his knowledge in the field of neuromuscular diseases, he joined Kevin Flanigan's team as a postdoctoral fellow in 2011, where he is currently working on two different muscular disorders.

What is the issue or problem addressed in your research?

Mutations in the DMD gene cause two muscular disorders, the severe DMD usually associated with stop mutations and the milder BMD. However, stop mutations within the first exon of this gene lead to a very mild BMD due to production of a nearly full-length and functional protein.

What methodology did you use in your research?

Cloning, molecular and cell biology, virus (AAV) production and exon-skipping will be used to achieve this study, as well as transdifferentiation of patient fibroblast into muscle cells.

What are the purpose/rationale and implications of your research?

This innovative project is of particular interest since it is the first time that an IRES element has been identified in the DMD gene, and interestingly, it seems to be active only in a muscle-dependent manner. In addition this project is a perfect example of an emerging research area, called translational research that is based on understanding pathophysiological processes by studying patient phenotypes according to their mutations. This had previously allowed to develop pertinent therapeutic strategies and according to our promising preliminary data, could again lead to an innovative therapeutic strategy (ies) that might be applicable for patients carrying mutations in exon 1 to 4. Finally, these results also underline the potential existence of another functional isoform of dystrophin, translated only in conditions of cell stress, as during muscle regeneration or after glucocorticoid treatment. This work presents an entirely new concept in the dystrophin field, and should serve as a catalyst to the DMD and basic muscle biology research communities in the search for meaningful therapies.