Tcn2, encoding transcobalamin II, is an essential plasma protein crucial for the absorption, transportation, and cellular uptake of vitamin B12 [3]. It is involved in one-carbon metabolism pathways, which are essential for various biological processes such as DNA synthesis, methylation reactions, and cell proliferation [2].

In zebrafish, loss-of-function of tcn2 leads to reduced growth in adult fish and severe developmental and metabolic defects in offspring from tcn2 -/- females, suggesting a maternal-effect contribution to early development [4]. In humans, TCN2 gene mutations cause transcobalamin II deficiency, presenting with symptoms like failure to thrive, pancytopenia, and immunodeficiency [3,5,7]. Additionally, TCN2 is associated with diseases like multiple sclerosis, where it functions in the FTY720-mediated B12-TCN2-CD320 signaling pathway to suppress neuroinflammation [1]. In systemic lupus erythematosus, elevated TCN2 in monocytes may promote disease progression by enhancing one-carbon flux, monocyte proliferation, and TLR4-mediated inflammation [6].

In conclusion, Tcn2 is vital for vitamin B12-related physiological processes. Gene knockout models in zebrafish and human genetic studies with TCN2 mutations have revealed its significance in growth, development, and disease. Its role in diseases such as multiple sclerosis, systemic lupus erythematosus, and transcobalamin II deficiency highlights its potential as a therapeutic target.

References:

1. Jonnalagadda, Deepa, Kihara, Yasuyuki, Groves, Aran, Rivera, Richard, Chun, Jerold. 2023. FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis. In Cell reports, 42, 113545. doi:10.1016/j.celrep.2023.113545. https://pubmed.ncbi.nlm.nih.gov/38064339/

2. Oussalah, Abderrahim, Levy, Julien, Filhine-Trésarrieu, Pierre, Namour, Fares, Guéant, Jean-Louis. 2017. Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies. In The American journal of clinical nutrition, 106, 1142-1156. doi:10.3945/ajcn.117.156349. https://pubmed.ncbi.nlm.nih.gov/28814397/

3. Kose, Engin, Besci, Ozge, Gudeloglu, Elif, Ozen, Selime, Isguder, Rana. . Transcobalamin II deficiency in twins with a novel variant in the TCN2 gene: case report and review of literature. In Journal of pediatric endocrinology & metabolism : JPEM, 33, 1487-1499. doi:10.1515/jpem-2020-0096. https://pubmed.ncbi.nlm.nih.gov/32841161/

4. Benoit, Courtney R, Walsh, Darren J, Mekerishvili, Levan, McGaughey, David M, Brody, Lawrence C. . Loss of the Vitamin B-12 Transport Protein Tcn2 Results in Maternally Inherited Growth and Developmental Defects in Zebrafish. In The Journal of nutrition, 151, 2522-2532. doi:10.1093/jn/nxab151. https://pubmed.ncbi.nlm.nih.gov/34132337/

5. Pongphitcha, Pongpak, Sirachainan, Nongnuch, Khongkraparn, Arthaporn, Songdej, Duantida, Wattanasirichaigoon, Duangrurdee. 2022. A novel TCN2 mutation with unusual clinical manifestations of hemolytic crisis and unexplained metabolic acidosis: expanding the genotype and phenotype of transcobalamin II deficiency. In BMC pediatrics, 22, 233. doi:10.1186/s12887-022-03291-5. https://pubmed.ncbi.nlm.nih.gov/35488219/

6. Liu, Baoyi, Li, Ang, Liu, Yi, Xue, Ke, Cui, Yong. 2024. Transcobalamin 2 orchestrates monocyte proliferation and TLR4-driven inflammation in systemic lupus erythematosus via folate one-carbon metabolism. In Frontiers in immunology, 15, 1339680. doi:10.3389/fimmu.2024.1339680. https://pubmed.ncbi.nlm.nih.gov/38881906/

7. Luo, Juan, Guo, Hongxi, Feng, Lifang, Yao, Hui, Chen, Xiaohong. 2022. Case report: Novel compound-heterozygous mutations in the TCN2 gene identified in a chinese girl with transcobalamin deficiency. In Frontiers in genetics, 13, 951007. doi:10.3389/fgene.2022.951007. https://pubmed.ncbi.nlm.nih.gov/36035190/