TMCO3, a member of the monovalent cation:proton antiporter-2 (CPA2) family, is predicted to function as a K⁺:proton antiporter. It has an N-terminal secretory signal peptide, forms a dimer in the membrane, and contains a CPA2 motif for K⁺ binding. TMCO3 is associated with the Golgi apparatus and may be involved in pathways related to growth regulation, cell cycle, epithelial-mesenchymal transition, and apoptosis [1,2].

In mice, Tmco3tm1b(KOMP)Wtsi knockout mice showed significant shortening of forelimbs and hindlimbs, indicating its importance for longitudinal growth [1]. In humans, a homozygous nonsense variant in TMCO3 was found in two sisters with isolated short stature, and the variant segregated with short stature in the family [1]. In hepatocellular carcinoma (HCC), upregulation of TMCO3 promotes tumor progression, affects sorafenib sensitivity, and is associated with immune cell infiltration and immune checkpoint gene expression [2,4]. In cervical cancer, circ_TMCO3 inhibits tumorigenicity via the miR-1291/FRMD6 axis [3].

In conclusion, TMCO3 is crucial for longitudinal growth in both mice and humans as shown by knockout models. In addition, it plays a role in cancer progression, making it a potential therapeutic target in diseases like HCC and cervical cancer. The study of TMCO3 through gene knockout models has provided insights into its function in growth-related and cancer-related biological processes.

References:

1. Holling, Tess, Brylka, Laura, Scholz, Tasja, Oheim, Ralf, Kutsche, Kerstin. 2023. TMCO3, a Putative K+ :Proton Antiporter at the Golgi Apparatus, Is Important for Longitudinal Growth in Mice and Humans. In Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 38, 1334-1349. doi:10.1002/jbmr.4827. https://pubmed.ncbi.nlm.nih.gov/37554015/

2. Dai, Tianxing, Ye, Linsen, Deng, Mingbin, Yang, Yang, Wang, Guoying. 2022. Upregulation of TMCO3 Promoting Tumor Progression and Contributing to the Poor Prognosis of Hepatocellular Carcinoma. In Journal of clinical and translational hepatology, 10, 913-924. doi:10.14218/JCTH.2021.00346. https://pubmed.ncbi.nlm.nih.gov/36304514/

3. Xue, Xue, Pan, Yixia, Li, Chen. 2024. Circ_TMCO3 Inhibits the Progression of Cervical Cancer by Activating FRMD6 Expression by Restraining miR-1291. In Reproductive sciences (Thousand Oaks, Calif.), 31, 2641-2653. doi:10.1007/s43032-024-01549-0. https://pubmed.ncbi.nlm.nih.gov/38700824/

4. Hu, Xinyao, Zhu, Hua, Feng, Shi, Ye, Yingze, Xiong, Xiaoxing. 2022. Transmembrane and coiled-coil domains 3 is a diagnostic biomarker for predicting immune checkpoint blockade efficacy in hepatocellular carcinoma. In Frontiers in genetics, 13, 1006357. doi:10.3389/fgene.2022.1006357. https://pubmed.ncbi.nlm.nih.gov/36246598/