Gnptab, encoding the α/β -subunit precursor of GlcNAc-1-phosphotransferase, is crucial for the mannose-6-phosphate pathway that targets catabolic enzymes to lysosomes [2,3,4,6,7]. This process is essential for proper lysosomal function, which is involved in various cellular catabolic processes, and its malfunction can lead to lysosomal storage disorders [4,5,6]. Genetic models, like mouse models, are valuable for studying Gnptab's function.

Engineering human stuttering-associated mutations into the mouse Gnptab gene resulted in vocalization deficits similar to human stuttering. Astrocyte-specific Gnptab-deficient mice also displayed the same vocalization deficit, indicating that vocalization defects in these mice stem from astrocyte abnormalities, especially in the corpus callosum [1]. In another study, Gnptab-deficient mice showed impaired bone remodeling and increased bone resorption, suggesting distinct molecular functions of GlcNAc-1-phosphotransferase subunits in bone cells [3].

In conclusion, Gnptab is vital for lysosomal enzyme trafficking. Mouse models with Gnptab mutations have revealed its role in vocalization and bone remodeling, providing insights into stuttering and mucolipidosis-related bone disorders. These studies enhance our understanding of the biological functions associated with Gnptab and the underlying mechanisms of related diseases.

References:

1. Han, Tae-Un, Root, Jessica, Reyes, Laura D, Barnes, Terra D, Drayna, Dennis. 2019. Human GNPTAB stuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum. In Proceedings of the National Academy of Sciences of the United States of America, 116, 17515-17524. doi:10.1073/pnas.1901480116. https://pubmed.ncbi.nlm.nih.gov/31405983/

2. Pechincha, Catarina, Groessl, Sven, Kalis, Robert, Zuber, Johannes, Palm, Wilhelm. 2022. Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins. In Science (New York, N.Y.), 378, eabn5637. doi:10.1126/science.abn5637. https://pubmed.ncbi.nlm.nih.gov/36074822/

3. Di Lorenzo, Giorgia, Westermann, Lena M, Yorgan, Timur A, Schinke, Thorsten, Pohl, Sandra. 2021. Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III. In Genetics in medicine : official journal of the American College of Medical Genetics, 23, 2369-2377. doi:10.1038/s41436-021-01285-9. https://pubmed.ncbi.nlm.nih.gov/34341521/

4. Wang, Ping, Mazrier, Hamutal, Caverly Rae, Jessica, Raj, Karthik, Giger, Urs. 2018. A GNPTAB nonsense variant is associated with feline mucolipidosis II (I-cell disease). In BMC veterinary research, 14, 416. doi:10.1186/s12917-018-1728-1. https://pubmed.ncbi.nlm.nih.gov/30591066/

5. Yang, Jingxin, Liu, Chao, Geng, Qian, Zhang, Lei, Wu, Weiqing. 2025. Two GNPTAB Variations Caused Mucolipidosis II Alpha/Beta in a Chinese Family. In Fetal and pediatric pathology, 44, 157-165. doi:10.1080/15513815.2025.2466057. https://pubmed.ncbi.nlm.nih.gov/39957256/

6. Ludwig, Nataniel Floriano, Velho, Renata Voltolini, Sperb-Ludwig, Fernanda, Pohl, Sandra, Schwartz, Ida Vanessa D. 2017. GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms. In The international journal of biochemistry & cell biology, 92, 90-94. doi:10.1016/j.biocel.2017.09.006. https://pubmed.ncbi.nlm.nih.gov/28918368/

7. Yang, Xi, Doray, Balraj, Venkatarangan, Varsha, Kornfeld, Stuart, Li, Ming. 2024. Molecular Insights into the Regulation of GNPTAB by TMEM251. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.12.05.627003. https://pubmed.ncbi.nlm.nih.gov/39677738/