<i>Gne</i> deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death

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