Tmx3, a member of the thioredoxin-related transmembrane (TMX) protein family, is an endoplasmic reticulum-luminal thiol-disulfide oxidoreductase of the protein disulfide-isomerase family [1,5]. It contains three thioredoxin-like domains, with the N-terminal domain being redox-active. Tmx3 is involved in processes like disulfide bond formation, protein folding and unfolding in the endoplasmic reticulum, which are crucial for protein maturation and quality control in eukaryotic cells [1].

In a study of left ventricular noncompaction (LVNC) and bicuspid aortic valve, Tmx3 was among the genes with variants cosegregating with MIB1 mutations in LVNC families. Quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice developed bicuspid aortic valve and other valve-associated defects, suggesting Tmx3 may have a role in the development of these cardiac diseases [2]. In Drosophila melanogaster Dα1/Dβ1 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes, Tmx3 was crucial for their functional expression [3]. In eye development, in-situ hybridization showed Tmx3 expression in the retinal and lens epithelium of developing murine eyes. Zebrafish morphant larvae with reduced Tmx3 expression had smaller eye sizes, and human wild-type Tmx3 mRNA could rescue this phenotype, indicating Tmx3's role in eye development [4].

In conclusion, Tmx3 is essential for protein-folding-related processes in the endoplasmic reticulum. Its role has been revealed in various disease-related and developmental processes through genetic models. In cardiac diseases like LVNC and bicuspid aortic valve, Tmx3 may contribute to disease development, and it also plays a role in eye development. These findings from model-based research enhance our understanding of Tmx3's functions and its implications in related diseases and biological processes [2-4].

References:

1. Guerra, Concetta, Molinari, Maurizio. 2020. Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5. In Cells, 9, . doi:10.3390/cells9092000. https://pubmed.ncbi.nlm.nih.gov/32878123/

2. Siguero-Álvarez, Marcos, Salguero-Jiménez, Alejandro, Grego-Bessa, Joaquim, Gimeno-Blanes, Juan R, de la Pompa, José Luis. 2022. A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve. In Circulation, 147, 47-65. doi:10.1161/CIRCULATIONAHA.121.058767. https://pubmed.ncbi.nlm.nih.gov/36325906/

3. Takayama, Koichi, Ito, Ryo, Yamamoto, Haruki, Matsuda, Kazuhiko, Ihara, Makoto. 2022. Effects of cofactors RIC-3, TMX3 and UNC-50, together with distinct subunit ratios on the agonist actions of imidacloprid on Drosophila melanogaster Dα1/Dβ1 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. In Pesticide biochemistry and physiology, 187, 105177. doi:10.1016/j.pestbp.2022.105177. https://pubmed.ncbi.nlm.nih.gov/36127041/

4. Chao, Ryan, Nevin, Linda, Agarwal, Pooja, Baier, Herwig, Slavotinek, Anne. 2010. A male with unilateral microphthalmia reveals a role for TMX3 in eye development. In PloS one, 5, e10565. doi:10.1371/journal.pone.0010565. https://pubmed.ncbi.nlm.nih.gov/20485507/

5. Haugstetter, Johannes, Maurer, Michael Andreas, Blicher, Thomas, Wider, Gerhard, Ellgaard, Lars. 2007. Structure-function analysis of the endoplasmic reticulum oxidoreductase TMX3 reveals interdomain stabilization of the N-terminal redox-active domain. In The Journal of biological chemistry, 282, 33859-33867. doi:10.1074/jbc.M706442200. https://pubmed.ncbi.nlm.nih.gov/17881353/