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. α1 is ubiquitously expressed and is the predominant paralog in peripheral axons [3,4].

In intermediate Charcot-Marie-Tooth (CMT) disease, two novel missense mutations in ATP1A1 (c.620C>T (p.S207F) and c.2629G>A (p.G877S)) were identified. These mutations led to loss of ATP1A1 protein function, downregulated its protein levels via proteasome degradation without affecting mRNA levels, thus confirming ATP1A1 as a novel causative gene for intermediate CMT [1]. In aldosterone-producing adenomas (APAs), the ATP1A1 L104R mutation stimulated cell proliferation, with higher Na/K-ATPase (NKA) expressions in ATP1A1-mutated APAs. The mutant also induced Src phosphorylation in ATP1A1-mutant cells [2]. Heterozygous Atp1a1+/- knockout mice were phenotypically normal up to 18 months, and a healthy human carrying a protein-null early truncation variant lacked clinical features of ATP1A1-related diseases, suggesting that a malfunctioning gene product is required for disease induction by ATP1A1 variants [3,4].

In summary, ATP1A1 is essential for maintaining transmembrane electrochemical gradients crucial for cell survival and electrical signaling. Studies using gene knockout models, like the Atp1a1+/- knockout mice, have provided insights into the role of ATP1A1 in diseases such as CMT and APAs, highlighting its significance in understanding the pathogenesis of these conditions.

References:

1. He, Jin, Guo, Lingling, Lin, Shan, Wang, Ning, Chen, Wanjin. 2019. ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease. In Human mutation, 40, 2334-2343. doi:10.1002/humu.23886. https://pubmed.ncbi.nlm.nih.gov/31373411/

2. Kobuke, Kazuhiro, Oki, Kenji, Gomez-Sanchez, Celso E, Hattori, Noboru, Yoneda, Masayasu. 2021. ATP1A1 Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation. In International journal of molecular sciences, 22, . doi:10.3390/ijms222010981. https://pubmed.ncbi.nlm.nih.gov/34681640/

3. Spontarelli, Kerri, Young, Victoria C, Sweazey, Ryan, Yano, Sho T, Artigas, Pablo. 2023. ATP1A1 -linked diseases require a malfunctioning protein product from one allele. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.03.05.531165. https://pubmed.ncbi.nlm.nih.gov/37090550/

4. Spontarelli, Kerri, Young, Victoria C, Sweazey, Ryan, Yano, Sho T, Artigas, Pablo. 2023. ATP1A1-linked diseases require a malfunctioning protein product from one allele. In Biochimica et biophysica acta. Molecular cell research, 1871, 119572. doi:10.1016/j.bbamcr.2023.119572. https://pubmed.ncbi.nlm.nih.gov/37659504/