Atp1a1, encoding the α1 subunit of the Na+/K+-ATPase (NKA), is a crucial gene. The NKA heterodimeric enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na+ and K+, which are essential for electrical signaling and cell survival. The α1 isoform is ubiquitously expressed and is the predominant paralog in peripheral axons [4,9].

Mutations in Atp1a1 have been linked to multiple diseases. In aldosterone-producing adenomas (APAs), the ATP1A1 L104R mutation leads to increased Na/K-ATPase (NKA) expression, stimulating cell proliferation and Src phosphorylation, suggesting NKA stimulations as a risk factor for APA development [1]. In intermediate Charcot-Marie-Tooth (CMT) disease, two novel missense mutations in ATP1A1 were identified, causing loss-of-function of the ATP1A1 protein through promoting its proteasome degradation [2]. A heterozygous ATP1A1 variant Gly903Arg causes developmental delay, intellectual disability, and autism, with reduced cell viability and loss of ATPase function [3]. De novo mutations in ATP1A1 are related to disorders with phenotypes like developmental delay, epilepsy, and hypomagnesemia, and mutations in different transmembrane regions of the ATP1A1 protein result in different severities of phenotypes [5]. In melanoma, high ATP1A1 expression is associated with reduced overall survival and resistance to BRAF inhibitor, and its ligand bufalin can target ATP1A1 to inhibit cell proliferation and tumor growth [6]. In myelomonocytic and monocytic acute myeloid leukemia, the ATP1A1/BCL2L1 expression ratio predicts the response to cardiac glycosides [7]. Also, somatic mutations in ATP1A1 are found in over 90% of aldosterone-producing adenomas [8].

In conclusion, Atp1a1 is essential for maintaining transmembrane electrochemical gradients via encoding the α1 subunit of NKA. Research on Atp1a1-related mutations in various disease models, such as those in APAs, CMT, and developmental disorders, has revealed its role in cell proliferation, neurological functions, and disease-associated phenotypes. These findings contribute to understanding the pathogenesis of related diseases and potentially developing new therapeutic strategies.