Amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL), encoded by the AGL gene, is primarily responsible for glycogen debranching. Mutations in this gene lead to glycogen storage disease type III (GSDIII), indicating its crucial role in glycogen metabolism [1,2,4]. Genetic models, such as knockout mice, can help in understanding its function.

In mice, germline Agl knockout (Agl-/-) and urothelium-specific conditional Agl knockout (Aglcko) mice, when exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), had a higher bladder cancer (BC) incidence compared to wild-type mice. This suggests that loss of Agl promotes carcinogenesis. RNA sequencing of tumors from Agl-/- mice identified 19 differentially expressed genes, and an 'Agl Loss' gene signature was developed, which could stratify normal and tumor samples in BC patient datasets [3].

In conclusion, AGL is essential for glycogen debranching, and its dysfunction is linked to GSDIII. The Agl KO/CKO mouse models have revealed its role in promoting bladder carcinogenesis, providing insights into the mechanisms of this disease and potentially guiding new strategies for its prevention and treatment.

References:

1. Zhang, Meng, Wang, Chang, Xie, Zhen, Wu, Cheng, Long, Yun. . [Analysis of two cases of glycogen storage disease type III due to compound heterozygous variants of AGL gene]. In Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics, 38, 1073-1076. doi:10.3760/cma.j.cn511374-20200803-00578. https://pubmed.ncbi.nlm.nih.gov/34729746/

2. Shindo, Akito, Ueda, Kazutaka, Minatsuki, Shun, Akazawa, Hiroshi, Komuro, Issei. 2023. Novel AGL variants in a patient with glycogen storage disease type IIIb and pulmonary hypertension caused by pulmonary veno-occlusive disease: A case report. In Frontiers in genetics, 14, 1148067. doi:10.3389/fgene.2023.1148067. https://pubmed.ncbi.nlm.nih.gov/37035733/

3. Sottnik, Joseph L, Mallaredy, Vandana, Chauca-Diaz, Ana, Clouthier, David, Theodorescu, Dan. . Elucidating the role of Agl in bladder carcinogenesis by generation and characterization of genetically engineered mice. In Carcinogenesis, 40, 194-201. doi:10.1093/carcin/bgy139. https://pubmed.ncbi.nlm.nih.gov/30403777/

4. Wang, Jing, Yu, Yuping, Cai, Chunquan, Zhao, Yu, Shu, Jianbo. 2022. The biallelic novel pathogenic variants in AGL gene in a chinese patient with glycogen storage disease type III. In BMC pediatrics, 22, 284. doi:10.1186/s12887-022-03252-y. https://pubmed.ncbi.nlm.nih.gov/35578201/