RTN2 (reticulon 2) is an endoplasmic reticulum (ER)-resident membrane shaping protein that regulates multiple cellular processes through its distinct structural domains and subcellular localization. The gene on chromosome 19.3 produces three protein isoforms (RTN2-A, RTN2-B, RTN2-C) through alternative splicing, with particularly high expression of the shortest transcript in skeletal muscle 1. RTN2 functions as a key regulator of intracellular calcium signaling by interacting with IP3 receptors to facilitate calcium release from the ER, subsequently activating ERK signaling pathways 2. The protein contains hydrophobic regions responsible for ER association and amino-terminal domains rich in negatively charged residues with multiple phosphorylation sites 1. Disease relevance is significant, as homozygous loss-of-function RTN2 variants cause autosomal recessive distal hereditary motor neuropathy with lower limb spasticity, characterized by early-onset weakness and slowly progressive disease course 3. Heterozygous mutations lead to autosomal dominant spastic paraplegia-12 (SPG12), presenting with variable phenotypes including visual abnormalities, seizures, and coordination dysfunction 4. Additionally, RTN2 overexpression promotes gastric cancer metastasis through ER calcium signaling and epithelial-to-mesenchymal transition 2, with its stability enhanced by O-GlcNAcylation post-translational modifications 5. RTN2 has also been identified as a potential circadian clock gene with elevated expression in ovarian cancer 6.