ATP1B4 encodes a protein that has undergone remarkable functional evolution in placental mammals. Originally functioning as a Na,K-ATPase beta-subunit in lower vertebrates, the ATP1B4 gene underwent co-option in eutherian mammals, where it lost its ancestral ion transport function 1. In placental mammals, ATP1B4 is predominantly expressed in muscle tissue and its protein product (BetaM) localizes to the inner nuclear membrane rather than the plasma membrane 1. BetaM functions as a transcriptional coregulator through direct interaction with the SKIP (Ski-interacting protein) transcriptional coregulator, regulating TGF-beta signaling pathways 1. The eutherian BetaM interactome has diversified to include interactions with nuclear lamina proteins (LAP-1, Syne1), heme oxygenases, and transcription factors, distinguishing it functionally from ancestral and avian orthologs 2. Regarding disease relevance, ATP1B4 variants showed no significant association with Parkinson's disease in a Chinese Han population 3. ATP1B4 fragments have been identified as potential biomarkers in endometriosis proteomics studies 4, and the gene appears as a differentially expressed gene in incisional hernia and atrial fibrillation pathogenesis studies 56. ATP1B4 is also implicated in microRNA regulation networks in tuberous sclerosis 7. However, no specific monogenic disease phenotypes have been definitively attributed to ATP1B4 mutations 8.