Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death

Abstract

The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gne^lox/lox gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreER^T2/Rosa-CreER^T2Gne^lox/lox mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreER^T2/+Gne^lox/lox mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gne^lox/lox mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.

Keywords: adeno associated virus; gene therapy; hematology; muscular dystrophy; sialic acid.