Tmcc2, transmembrane and coiled-coil domain 2, is an endoplasmic reticulum-residing transmembrane protein. Its physiological functions are being increasingly explored, with potential involvements in multiple biological pathways. It has been associated with processes like erythropoiesis, inner ear hair cell function, and may be linked to neurodegenerative diseases through its interactions with proteins such as amyloid protein precursor (APP) and apolipoprotein E (apoE) [2,3,4,5]. Genetic models, especially knockout mouse models, are crucial for understanding its functions in vivo.

In gene knockout mouse models, Tmcc2 -/- pups exhibit profound neonatal macrocytic anemia with numerous nucleated RBCs and occasional multinucleated RBCs, indicating its requirement for normal erythropoiesis. Adult knockouts show normocytic, mildly polycythemic phenotypes with active extramedullary erythropoiesis in the spleen, suggesting a defect in erythroid maturation at the polychromatic to orthochromatic transition stage [1]. Tmcc2 knockout mice also suffer from congenital hearing loss due to progressive auditory hair cell loss, with increased endoplasmic reticulum stress observed [2]. In Drosophila, the orthologue of Tmcc2, Dementin, interacts with APP and its Drosophila orthologue, and its disruption affects neurodegeneration [3].

In conclusion, Tmcc2 is essential for normal erythropoiesis and auditory hair cell function. Gene knockout mouse models have revealed its significant roles in these biological processes. The associations in neurodegenerative-related studies also suggest its potential importance in understanding the pathogenesis of diseases like Alzheimer's disease. Overall, Tmcc2-related research contributes to our understanding of multiple physiological and disease-related mechanisms [1,2,3].

References:

1. Kumari, Ranju, Grzywa, Tomasz M, Małecka-Giełdowska, Milena, Nowis, Dominika, Kaźmierczak, Piotr. 2022. Ablation of Tmcc2 Gene Impairs Erythropoiesis in Mice. In International journal of molecular sciences, 23, . doi:10.3390/ijms23095263. https://pubmed.ncbi.nlm.nih.gov/35563652/

2. Ren, Rui, Xing, Haiyue, Wang, Xiaoying, Wang, Yanfei, Xu, Zhigang. . Loss of TMCC2 activates endoplasm reticulum stress and causes auditory hair cell death. In Human molecular genetics, 32, 1622-1633. doi:10.1093/hmg/ddad003. https://pubmed.ncbi.nlm.nih.gov/36617157/

3. Hopkins, Paul C R. 2013. Neurodegeneration in a Drosophila model for the function of TMCC2, an amyloid protein precursor-interacting and apolipoprotein E-binding protein. In PloS one, 8, e55810. doi:10.1371/journal.pone.0055810. https://pubmed.ncbi.nlm.nih.gov/23409049/

4. Hopkins, Paul C R, Sáinz-Fuertes, Ricardo, Lovestone, Simon. . The impact of a novel apolipoprotein E and amyloid-β protein precursor-interacting protein on the production of amyloid-β. In Journal of Alzheimer's disease : JAD, 26, 239-53. doi:10.3233/JAD-2011-102115. https://pubmed.ncbi.nlm.nih.gov/21593558/

5. Hopkins, Paul C R, Troakes, Claire, King, Andrew, Tear, Guy. 2024. Transmembrane and coiled-coil 2 associates with Alzheimer's disease pathology in the human brain. In Brain pathology (Zurich, Switzerland), 35, e13290. doi:10.1111/bpa.13290. https://pubmed.ncbi.nlm.nih.gov/39084860/