Gnptab-flox Mouse

Gnptab, encoding the α/β -subunit precursor of GlcNAc-1-phosphotransferase, is crucial for the targeting of catabolic enzymes to lysosomes through mannose-6-phosphate modification. This process is part of the lysosomal enzyme trafficking pathway, which is essential for normal cellular function and catabolism of various substances [2,3,4,5].

Engineering human stuttering-associated mutations into the mouse Gnptab gene led to vocalization deficits similar to human stuttering, along with astrocyte pathology in the corpus callosum. Only astrocyte-specific Gnptab-deficient mice displayed a similar vocalization deficit, suggesting that the vocalization defects in these mice are due to astrocyte abnormalities [1]. In addition, pathogenic variants in Gnptab cause mucolipidosis (ML) II and MLIII alpha/beta, and in patients with GNPTAB-associated MLIII alpha/beta, bone remodeling is impaired with increased bone resorption [3]. A nonsense variant in Gnptab causes feline mucolipidosis II, and missense mutations in Gnptab lead to loss of GlcNAc-1-phosphotransferase activity in human MLII patients [4,5].

In conclusion, Gnptab is essential for lysosomal enzyme trafficking. Mouse models with Gnptab mutations have revealed its role in vocalization through astrocyte-related mechanisms and in bone remodeling in mucolipidosis. These model-based studies contribute to understanding the pathophysiology of stuttering and mucolipidosis, providing insights for potential therapeutic approaches.