Atp1a1, encoding the α1 subunit of the Na+/K+-ATPase (NKA), is a crucial gene. The heterodimeric NKA enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na+ and K+ essential for electrical signaling and cell survival. Among the 4 catalytic subunit isoforms, α1 is ubiquitously expressed and is the predominant paralog in peripheral axons [4,6].

Mutations in Atp1a1 have been linked to various diseases. In aldosterone-producing adenomas (APAs), the ATP1A1 L104R mutation stimulates cell proliferation, with increased Na/K-ATPase (NKA) expression, cell number, DNA amount, S-phase population, and Src phosphorylation [1]. In intermediate Charcot-Marie-Tooth (CMT) disease, two novel missense mutations in ATP1A1 lead to loss-of-function of the ATP1A1 protein, downregulating its protein levels [2]. A recurrent ATP1A1 variant Gly903Arg causes developmental delay, intellectual disability, and autism, with significantly reduced cell viability and loss of ATPase function [3]. ATP1A1-linked diseases generally require a malfunctioning protein product from one allele, as heterozygous Atp1a1+/- knockout mice were phenotypically normal up to 18 months of age, and a healthy adult human with a protein-null early truncation variant lacked disease features [4,6]. De novo ATP1A1 mutations are related to disorders with developmental delay, often accompanied by epilepsy. Variants in different transmembrane regions of the ATP1A1 protein result in different severities of phenotypes [5].

In conclusion, Atp1a1 is essential for maintaining transmembrane electrochemical gradients through its role in encoding the α1 subunit of NKA. Research on Atp1a1, including through gene knockout models, has revealed its significant contributions to diseases such as APAs, CMT, and various neurodevelopmental disorders, enhancing our understanding of disease mechanisms related to this gene.