Atp1a1-flox Mouse

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 +, which are essential for electrical signaling and cell survival. The α1 isoform is ubiquitously expressed and is the predominant paralog in peripheral axons [4,5].

In aldosterone-producing adenomas (APAs), the ATP1A1 L104R mutation leads to increased Na/K-ATPase (NKA) expressions, stimulating cell proliferation and Src phosphorylation. NKA stimulations might be a risk factor for the development of ATP1A1 mutant APA [1].

In intermediate Charcot-Marie-Tooth (CMT) disease, two novel missense mutations in ATP1A1 were identified, leading to loss-of-function of the ATP1A1 protein by promoting its proteasome degradation [2]. A recurrent ATP1A1 variant Gly903Arg causes developmental delay, intellectual disability, and autism, with significantly reduced cell viability and loss of ATPase function [3].

Heterozygous Atp1a1 +/- knockout mice were phenotypically normal up to 18 months of age, suggesting that a malfunctioning gene product is required for disease induction by ATP1A1 variants [4,5].

In conclusion, Atp1a1 is essential for maintaining transmembrane electrochemical gradients through the function of NKA. Studies using gene knockout models, like the Atp1a1 +/- knockout mice, have provided insights into its role in diseases such as APAs, CMT, and neurodevelopmental disorders, helping to understand the mechanisms of disease occurrence related to Atp1a1 malfunction.