Car2, or carbonic anhydrase 2, encodes the primary isoenzyme responsible for aqueous humor (AH) production, playing a major role in intraocular pressure (IOP) regulation [1]. It is also involved in other biological processes in different organisms, such as the regulation of Dictyostelium discoideum development as a prestalk cAMP receptor [2]. In Saccharomyces cerevisiae, CAR2 encodes ornithine transaminase, an arginine-degradative enzyme [3].

In a glaucoma study, CRISPR-Cas9-mediated deletion of Car2 in the ciliary body of mice significantly and sustainably reduced IOP by inhibiting AH production, delaying and even halting glaucomatous damage in a chronic ocular hypertension model, outperforming clinically available carbonic anhydrase inhibitors [1]. In Car2-deficient (Car2-/-) mice, the expression of Car9 was up-regulated in the stomach, suggesting a compensatory mechanism [4]. In mouse placental overgrowth models, although homozygous deletion of Car2 did not result in placental phenotypes, Car3, which may take over the function of Car2, was expressed in the spongiotrophoblast of Car2 mutant placentas, indicating a possible rescue mechanism [5].

In conclusion, Car2 has essential functions in aqueous humor production and IOP regulation, with implications for glaucoma treatment as shown by gene-knockout mouse models. It also participates in other biological processes like yeast metabolism and mouse placental development, where knockout models have provided insights into potential compensatory and rescue mechanisms.

References:

1. Jiang, Jiaxuan, Kong, Kangjie, Fang, Xiuli, Yu-Wai-Man, Patrick, Zhang, Xiulan. 2024. CRISPR-Cas9-mediated deletion of carbonic anhydrase 2 in the ciliary body to treat glaucoma. In Cell reports. Medicine, 5, 101524. doi:10.1016/j.xcrm.2024.101524. https://pubmed.ncbi.nlm.nih.gov/38670096/

2. Saxe, C L, Ginsburg, G T, Louis, J M, Devreotes, P N, Kimmel, A R. . CAR2, a prestalk cAMP receptor required for normal tip formation and late development of Dictyostelium discoideum. In Genes & development, 7, 262-72. doi:. https://pubmed.ncbi.nlm.nih.gov/8436297/

3. Park, H D, Scott, S, Rai, R, Dorrington, R, Cooper, T G. . Synergistic operation of the CAR2 (Ornithine transaminase) promoter elements in Saccharomyces cerevisiae. In Journal of bacteriology, 181, 7052-64. doi:. https://pubmed.ncbi.nlm.nih.gov/10559172/

4. Pan, Peiwen, Leppilampi, Mari, Pastorekova, Silvia, Sly, William S, Parkkila, Seppo. 2006. Carbonic anhydrase gene expression in CA II-deficient (Car2-/-) and CA IX-deficient (Car9-/-) mice. In The Journal of physiology, 571, 319-27. doi:. https://pubmed.ncbi.nlm.nih.gov/16396925/

5. Singh, Umashankar, Sun, Tong, Shi, Wei, Wakayama, Teruhiko, Fundele, Reinald. . Expression and functional analysis of genes deregulated in mouse placental overgrowth models: Car2 and Ncam1. In Developmental dynamics : an official publication of the American Association of Anatomists, 234, 1034-45. doi:. https://pubmed.ncbi.nlm.nih.gov/16247769/