P152 Post weaning Gne knock out results in dramatic reduction of sialic acid levels in postnatal mouse life but no phenotype

GNE Myopathy is a unique neuromuscular adult onset disease characterized by slowly progressive distal and proximal muscle weakness, caused by recessive mutations in GNE. Although the function of this protein is known to be a key enzyme in the biosynthesis of sialic acid, no clear definite explanation has been provided to account for the muscle atrophic pathology. The lack of animal models severely impair the comprehensive understanding of GNE function, and, more importantly, prevents the development of an efficient system to assess any kind of treatment. Since a complete knockout of the Gne gene is embryonically lethal, we have recently generated an inducible muscle specific Gne knockout (KO) conditional mouse, where Gne can be knocked out postnatally, after Cre activation. Since the liver is the main source of sialylated glycoconjugates in the serum, that could be a source of sialic acid supply in the organism, in particular muscle, we generated double tissue post weaning Gne KO in both muscle and liver, to minimize the potential supply of sialic acid to muscle through the serum. Indeed 4 weeks post Cre induction, Gne abrogation at both DNA and protein levels is noticeable in the targeted tissues, resulting in a dramatic reduction of sialic acid levels in these tissues. However, these mice show no changes in survival and very mild changes in muscle function, motility, saturated oxygen levels and histology. No correlation between sialic acid content and muscle defects was observed. Interestingly, Gne KO in liver, which does lower dramatically sialic acid levels, does not affect the viability of the mice or their behavior and performance. This could suggest that sialic acid is not essential in post weaning mice. However, it could be that some minimal residual sialic acid potentially supplied from other tissues, is enough to support these mice life. Therefore, a post weaning whole body Gne KO should be generated to answer this question and to potentially produce a mouse with muscle pathology. Such a model could provide better insights for Gne functions in muscle and could eventually be used as a platform for therapy evaluation for this crippling disease. GNE Myopathy is a unique neuromuscular adult onset disease characterized by slowly progressive distal and proximal muscle weakness, caused by recessive mutations in GNE. Although the function of this protein is known to be a key enzyme in the biosynthesis of sialic acid, no clear definite explanation has been provided to account for the muscle atrophic pathology. The lack of animal models severely impair the comprehensive understanding of GNE function, and, more importantly, prevents the development of an efficient system to assess any kind of treatment. Since a complete knockout of the Gne gene is embryonically lethal, we have recently generated an inducible muscle specific Gne knockout (KO) conditional mouse, where Gne can be knocked out postnatally, after Cre activation. Since the liver is the main source of sialylated glycoconjugates in the serum, that could be a source of sialic acid supply in the organism, in particular muscle, we generated double tissue post weaning Gne KO in both muscle and liver, to minimize the potential supply of sialic acid to muscle through the serum. Indeed 4 weeks post Cre induction, Gne abrogation at both DNA and protein levels is noticeable in the targeted tissues, resulting in a dramatic reduction of sialic acid levels in these tissues. However, these mice show no changes in survival and very mild changes in muscle function, motility, saturated oxygen levels and histology. No correlation between sialic acid content and muscle defects was observed. Interestingly, Gne KO in liver, which does lower dramatically sialic acid levels, does not affect the viability of the mice or their behavior and performance. This could suggest that sialic acid is not essential in post weaning mice. However, it could be that some minimal residual sialic acid potentially supplied from other tissues, is enough to support these mice life. Therefore, a post weaning whole body Gne KO should be generated to answer this question and to potentially produce a mouse with muscle pathology. Such a model could provide better insights for Gne functions in muscle and could eventually be used as a platform for therapy evaluation for this crippling disease.