Rtn2, or Reticulon-2, is an endoplasmic reticulum (ER)-resident membrane shaping protein. It may be involved in the circadian rhythm as a potential circadian clock gene [3], and in lipid metabolism-related pathways in colon adenocarcinoma [4]. In maize endosperm, Rtn2 modulates autophagy of the ER, interacting with Atg8a and being crucial for ER homeostasis and suppression of ER stress [7].

Homozygous loss-of-function RTN2 variants in humans lead to an autosomal recessive distal motor neuropathy with lower limb spasticity. Affected individuals show distal upper and lower limb weakness, lower limb spasticity, and hyperreflexia starting in the first decade of life. Nerve conduction studies indicate axonal motor neuropathy. In Caenorhabditis elegans, homologous loss-of-function variants cause morphological and behavioral differences, and treatment with an ER Ca2+ reuptake inhibitor can rescue key phenotypic differences [1]. In SPG12 patients with RTN2 mutations, abnormal subcellular localization of mutant Reticulon-2 and improper ER morphogenesis result in phenotypic heterogeneity, presenting classic SPG symptoms along with additional features like visual abnormalities, sphincter disturbances, or seizures [2]. In gastric cancer, RTN2 promotes metastasis by activating endoplasmic reticulum Ca2+ efflux-mediated ERK signalling, and its O-GlcNAcylation enhances protein stability and its oncogenic functions [5,6].

In conclusion, Rtn2 is essential for maintaining normal cellular functions, especially related to the ER. Studies on loss-of-function models, both in worms and humans, have revealed its role in motor neuropathies and cancer-related processes, such as metastasis in gastric cancer. Understanding Rtn2 function provides insights into the pathogenesis of these diseases and may guide the development of potential therapeutic strategies.

References:

1. Maroofian, Reza, Sarraf, Payam, O'Brien, Thomas J, Nagy, Sara, Houlden, Henry. . RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity. In Brain : a journal of neurology, 147, 2334-2343. doi:10.1093/brain/awae091. https://pubmed.ncbi.nlm.nih.gov/38527963/

2. Tian, Wotu, Zheng, Haoran, Zhu, Zeyu, Luan, Xinghua, Cao, Li. 2022. New phenotype of RTN2-related spectrum: Complicated form of spastic paraplegia-12. In Annals of clinical and translational neurology, 9, 1108-1115. doi:10.1002/acn3.51605. https://pubmed.ncbi.nlm.nih.gov/35684947/

3. Zheng, Xiaojiao, Lv, Xiuyi, Chai, Jinghan, Zhu, Linyan, Zhang, Xianning. 2022. RTN2, a new member of circadian clock genes identified by database mining and bioinformatics prediction, is highly expressed in ovarian cancer. In Molecular medicine reports, 26, . doi:10.3892/mmr.2022.12866. https://pubmed.ncbi.nlm.nih.gov/36177918/

4. Jiang, Chunhui, Liu, Ye, Wen, Siyuan, Xu, Chunjie, Gu, Lei. 2021. In silico development and clinical validation of novel 8 gene signature based on lipid metabolism related genes in colon adenocarcinoma. In Pharmacological research, 169, 105644. doi:10.1016/j.phrs.2021.105644. https://pubmed.ncbi.nlm.nih.gov/33940186/

5. Wang, Gaojia, Xu, Zhijian, Sun, Jie, Gu, Jianxin, Song, Shushu. 2023. O-GlcNAcylation enhances Reticulon 2 protein stability and its promotive effects on gastric cancer progression. In Cellular signalling, 108, 110718. doi:10.1016/j.cellsig.2023.110718. https://pubmed.ncbi.nlm.nih.gov/37196774/

6. Song, Shushu, Liu, Bo, Zeng, Xiaoqing, Ruan, Yuanyuan, Wang, Hongshan. 2022. Reticulon 2 promotes gastric cancer metastasis via activating endoplasmic reticulum Ca2+ efflux-mediated ERK signalling. In Cell death & disease, 13, 349. doi:10.1038/s41419-022-04757-1. https://pubmed.ncbi.nlm.nih.gov/35428758/

7. Zhang, Xiaoguo, Ding, Xinxin, Marshall, Richard Scott, Vierstra, Richard David, Otegui, Marisa S. 2020. Reticulon proteins modulate autophagy of the endoplasmic reticulum in maize endosperm. In eLife, 9, . doi:10.7554/eLife.51918. https://pubmed.ncbi.nlm.nih.gov/32011236/