G6pc3, also known as glucose-6-phosphatase catalytic subunit 3, encodes the ubiquitously expressed glucose-6-phosphatase enzyme (G-6-Pase β or G-6-Pase 3). It is involved in regulating cytoplasmic glucose availability and is part of the glycogenolytic pathway. G6pc3 also functions as a neutrophil metabolite repair enzyme, hydrolyzing 1,5-anhydroglucitol-6-phosphate, a toxic metabolite [3,4].

Using CRISPR-Cas9 technology, G6pc3 -knockout (KO) mice were generated. In these KO mice, there was complete meiotic arrest at the pachytene stage in spermatocytes, leading to sterility. Abnormal XY body formation and impaired meiotic sex chromosome inactivation (MSCI) were also observed, indicating G6pc3 is essential for meiotic progression in male spermatogenesis [1]. In G6pc3 -deficient mice, failure to eliminate 1,5-anhydroglucitol-6-phosphate leads to neutrophil dysfunction and death, and treatment with sodium glucose cotransporter 2 (SLGT2) inhibitor restores the neutrophil count [2].

In conclusion, G6pc3 plays a crucial role in multiple biological processes. Its function in maintaining meiotic sex chromosome inactivation during spermatogenesis and its role in preventing neutrophil dysfunction are significant. Studies using G6pc3 KO mouse models have provided insights into these functions and have implications for understanding male infertility and conditions related to neutropenia, such as severe congenital neutropenia type 4 [1,2,3].

References:

1. Cao, Yuming, Wang, Shengnan, Li, Liyang, Wei, Zexiao, Wang, Li. . G6PC3 is involved in spermatogenesis by maintaining meiotic sex chromosome inactivation. In Acta biochimica et biophysica Sinica, 57, 286-294. doi:10.3724/abbs.2024172. https://pubmed.ncbi.nlm.nih.gov/39420835/

2. Hiwarkar, Prashant, Bargir, Umair, Pandrowala, Ambreen, Madkaikar, Manisha, Desai, Mukesh. 2022. SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency. In Journal of clinical immunology, 42, 1653-1659. doi:10.1007/s10875-022-01323-4. https://pubmed.ncbi.nlm.nih.gov/35838821/

3. Banka, Siddharth, Newman, William G. 2013. A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations. In Orphanet journal of rare diseases, 8, 84. doi:10.1186/1750-1172-8-84. https://pubmed.ncbi.nlm.nih.gov/23758768/

4. Dienel, Gerald A. 2020. Hypothesis: A Novel Neuroprotective Role for Glucose-6-phosphatase (G6PC3) in Brain-To Maintain Energy-Dependent Functions Including Cognitive Processes. In Neurochemical research, 45, 2529-2552. doi:10.1007/s11064-020-03113-z. https://pubmed.ncbi.nlm.nih.gov/32815045/