P.28 Introduction of 12 novel pathogenic DMD variants, associated phenotypes and studies of dystrophin and MAST1 abundances

Abstract

Duchenne muscular dystrophy (DMD) affects one in 3,500-5,600 of male newborns, making it the most common inherited muscular dystrophy. Becker muscular dystrophy (BMD), its milder form, is much rarer, affecting only one in about 18,000 male newborns. Both are caused by different types of mutations in the <i>DMD</i> gene. The encoded protein dystrophin stabilises the plasma membrane of the muscle cell as part of the dystrophin-glycoprotein-complex. Current research into DMD and BMD can explain about 92% of the phenotypes based on their genotypes through the frame-shift hypothesis. However, the remaining 8% are not adequately explained by this hypothesis, so that there is a need for further research to explain - not only - intermediate courses. We screened the cohort of DMD and BMD patients treated at the department of pediatric neurology of the University Hospital Essen for novel pathogenic <i>DMD</i> variants and corresponding phenotypes. We analysed the protein signatures (including post-translational modifications), measured dystrophin levels and studied the interactions of dystrophin and MAST1 in different biomaterials. Here, we report on 12 novel pathogenic variants, which have not yet been described in literature and link though to several several atypical phenotypes. Clinical findings were correlated with abundances of dystrophin and MAST1 toward an attempt of patient stratification. Knowing about novel genotypes and its corresponding (evolving) phenotype is very important in terms of counselling of affected families. Analysing the protein signatures and dystrophin levels as well as interaction partners is crucial to better understand the pathophysiology of dystrophin expression, especially in view of the development of new therapeutic approaches.