Adgrg6, also known as GPR126, is an adhesion G protein-coupled receptor (aGPCR) belonging to the GPCR superfamily. It has critical roles in developmental processes such as Schwann cell maturation and inner ear morphogenesis in zebrafish embryos [1,2]. In mammals, it is involved in Schwann cell-mediated myelination in the peripheral nervous system [2]. It may also be associated with pathways like cAMP-PKA signaling [3]. Genetic models like the zebrafish have been valuable for studying Adgrg6 [1].

In zebrafish, homozygous adgrg6 hypomorphic mutants have been used as a screening platform. This has helped identify candidate molecules that can influence Adgrg6 signaling activity and rescue mutant phenotypes, offering promise as small-molecule modulators of the Adgrg6 pathway [1]. In human studies, mutations in the ADGRG6 gene can lead to severe deficits in peripheral myelination, and variants are associated with diseases such as lung cancer, bladder cancer, and arthrogryposis multiplex congenita [3,4,5]. In lung cancer, a non-coding SNP rs1663689 can repress ADGRG6 expression, reducing downstream cAMP-PKA signaling and tumor growth [3]. In bladder cancer, ADGRG6 enhancer hotspot mutations are present at a high rate, potentially serving as a diagnostic biomarker [5].

In conclusion, Adgrg6 is essential for developmental processes, especially in myelination. Model-based research, such as using zebrafish mutants, has revealed its role in various biological functions and disease conditions. Its association with diseases like lung and bladder cancer shows its potential as a therapeutic target in these disease areas.

References:

1. Baxendale, Sarah, Asad, Anzar, Shahidan, Nahal O, Wiggin, Giselle R, Whitfield, Tanya T. 2021. The adhesion GPCR Adgrg6 (Gpr126): Insights from the zebrafish model. In Genesis (New York, N.Y. : 2000), 59, e23417. doi:10.1002/dvg.23417. https://pubmed.ncbi.nlm.nih.gov/33735533/

2. Li, Qi, Huo, Anran, Li, Mengqi, Cui, Hengxiang, Cong, Qifei. 2023. Structure, ligands, and roles of GPR126/ADGRG6 in the development and diseases. In Genes & diseases, 11, 294-305. doi:10.1016/j.gendis.2023.02.016. https://pubmed.ncbi.nlm.nih.gov/37588228/

3. Lei, Xinyue, Tian, Xiaoling, Wang, Hao, Ma, Zhenyi, Liu, Zhe. 2023. Noncoding SNP at rs1663689 represses ADGRG6 via interchromosomal interaction and reduces lung cancer progression. In EMBO reports, 24, e56212. doi:10.15252/embr.202256212. https://pubmed.ncbi.nlm.nih.gov/37154297/

4. Laquerriere, Annie, Jaber, Dana, Abiusi, Emanuela, Gitiaux, Cyril, Melki, Judith. 2021. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita. In Journal of medical genetics, 59, 559-567. doi:10.1136/jmedgenet-2020-107595. https://pubmed.ncbi.nlm.nih.gov/33820833/

5. Tan, Dan, Jiang, Wenqi, Hu, Rixin, Li, Zhuoran, Ou, Tong. 2023. Detection of the ADGRG6 hotspot mutations in urine for bladder cancer early screening by ARMS-qPCR. In Cancer medicine, 12, 11503-11512. doi:10.1002/cam4.5879. https://pubmed.ncbi.nlm.nih.gov/37081791/