P.188 Early growth and metabolic abnormalities in zebrafish and cellular models of SELENON-related myopathy

Abstract

SELENON-Related Myopathy (SELENON-RM) is a rare genetic disease caused by recessive mutations of the <i>SELENON</i> gene. It is characterized by the development of rigid spine, axial muscle weakness, and respiratory insufficiency. The most common histopathological feature in SELENON-RM patients is the presence of minicores in skeletal muscle biopsies, which are concentrated areas of mitochondrial depletion within fibers. Natural history data suggest that insulin-resistance as well as altered body mass index (BMI) are correlated with SELENON-RM prognosis. There is no cure or effective treatment for SELENON-RM. The <i>SELENON</i> gene encodes selenoprotein-N, an endoplasmic reticulum (ER) membrane glycoprotein with reducing catalytic activity. Selenoprotein-N has been shown to activate SERCA channels by reducing it at low Ca²⁺ concentrations in the ER. Additionally, it has also been shown to colocalize with Mitochondrial Associated Membranes (MAM), which are vital for mitochondrial function. However, the molecular mechanism(s) by which selenoprotein-N deficiency causes SELENON-RM is still unclear. A particular challenge has been the lack of cellular or animal models that exhibit readily assayable phenotypes. In this project, we aim to identify cellular and animal models suited for high throughput drug screening while elucidating the molecular mechanism of the disease. To do so, we tested selenoprotein-N deficient cells and zebrafish selenon-null models. Using different measures of metabolism, we found that Selenon-KO C2C12 cells and primary myoblasts isolated from Selenon-KO mice were metabolically impaired. We also assessed several phenotyping outcomes in zebrafish models, from embryonic development to adulthood. Our results showed muscle weakness during early development as well as reduced growth during the larval stage. Together, these data establish the potential for selenoprotein-N deficient cells and zebrafish as models for the discovery of therapeutic targets for SELENON-RM.