Final Activity Report Summary - MYO-PATHOGENESIS (Gene discovery and disease pathogenesis in the inherited myopathies.) The inherited myopathies are a diverse group of disorders resulting in significant morbidity, and hence significant health care costs, due to loss of mobility and respiratory failure. There is a wide spectrum of clinical severity, ranging from death in the newborn period, through to adult onset cases with slow progression of weakness. The congenital myopathies are usually defined on morphological grounds, based on the presence of distinctive changes in the muscle fibre. This group includes nemaline myopathy, central core disease, congenital fibre type disproportion (CFTD), multiminicore disease, myotubular myopathy and SEPN1-related myopathy. Mutations in the selenoprotein N gene (SEPN1) lead to at least four congenital myopathies that are grouped under the name SEPN1-related myopathy. These congenital myopathies were originally considered to be separate entities based on their histological characteristics, even though patients shared the common clinical phenotype of weakness of axial muscles leading to respiratory insufficiency and generalised atrophy. A large number of disease genes were identified for the inherited myopathies over the last 10 years or so. The laboratories of Drs North and Guicheney played an internationally leading role in many of these gene discoveries and had an extensive collection of patient diagnostic specimens for further gene discovery projects. The first aim of my project was to investigate the genetic basis of inherited myopathies through identification of novel genes or molecular mechanisms. I participated in the identification of a large duplication and deletion in the LARGE gene of two sisters presenting moderate mental retardation and cerebellar malformations together with dystrophic changes and markedly reduced alpha-dystroglycan glycosylation staining on muscle biopsy. We identified, along with a colleague, the size of the duplication, searched for its intronic location and the breakpoints and found a more complex rearrangement than initially thought which was associated with an intronic deletion. The second aim of my project was to explore pathogenetic mechanisms of weakness in inherited myopathies. During my fellowship, I worked on four main diseases, namely nemaline myopathy and mitochondrial disorders, congenital fiber type disproportion (CFTD) and selenoprotein N related myopathies. Through the application of different techniques of physiology, cellular and molecular biology I was able to explore the different mechanisms underlying these pathologies. This research had an immediate application to clinical practice in term of diagnostic accuracy, genetic counselling and prenatal diagnosis. This work also provided new and important information concerning normal skeletal biology and disease pathogenesis as the basis for the development of specific therapies. My work during these three years led to the publication of one first author paper and two co-author papers in international peer-reviewed journals. Another co-author paper was submitted and two others were in preparation by the time of the project completion. I finally presented my work during seven international congresses either by oral communications or by poster.