Résumé :
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Communication n° 296 Mutations in the Selenoprotein N gene (SEPN1) are the cause for different forms of congenital muscular dystrophies: Rigid Spine Muscular Dystrophy, Multiminicore Disease and Mallory-Body like Desmin Related Myopathy, now collectively named SePN-related myopathies. These diseases are characterized by an early onset of hypotonia, predominance of axial muscle weakness leading to life-threatening respiratory insufficiency and scoliosis. We showed previously that SePN is a selenium containing protein; it is a trans-membrane glycoprotein of the endoplasmic reticulum with an early developmental expression pattern. However, the precise role of SePN in muscle formation, activity or maintenance, has to be further investigated, since its biochemical function is unknown yet. Two approaches have been conducted to answer this question. Recombinant forms of SePN associated to high-performance affinity purification experiments were performed to identify associated partners or substrates. In parallel, development of a transgenic animal model of the disease consisting in a conditional knockout of SEPN1 is currently underway. So far, we found that SePN interacts in vivo to form a 120kDa complex. The interacting partner(s) will be characterized by mass spectrometry. Identification of a protein of known function would be a valuable hint, which will allow us to test possible SePN functions, in regard to its implication in the emergence of the muscular syndromes. Moreover, we produced high amounts of recombinant SePN in bacteria for structure-function studies. We also already obtained several heterozygous mice, genetically modified for SEPN1. Taking advantage of the Cre-Lox system, we will obtain either a total knockout mouse for the gene, or a conditional deletion in specific tissues, like muscles. Analysis of these transgenic mice will help to address the physiological aspects of the diseases, notably at early embryonic development stages. Deciphering SePN role will be useful to unravel the molecular, cellular and physiopathological processes precluding the emergence of the muscular disease. The final goal of understanding SePN-related myopathies both at molecular and physiological levels is to develop accurate diagnosis and targeted therapeutic approaches, derived from predictive modeling and simulation tools.
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