C57BL/6JCya-Atp1a2^em1flox/Cya

Atp1a2, encoding the α2 isoform of the Na⁺,K⁺ -ATPase's catalytic subunit, is an integral plasma membrane protein of the P-type ATPase family. It maintains sodium (Na⁺) and potassium (K⁺) gradients across cellular membranes by hydrolyzing ATP, which is crucial for ion channel and transporter activities involved in neuronal excitability, neurotransmitter uptake, and Ca²⁺ signaling [3,4].

Constitutional heterozygous mutations of ATP1A2 are associated with familial hemiplegic migraine, while homozygous truncating mutations are linked to early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria. In a study, 6 out of 22 patients with developmental and epileptic encephalopathies variably associated with cortical development malformations had de novo or inherited heterozygous ATP1A2 mutations. These patients often had early-onset seizures, and some had polymicrogyria, with severe phenotypes resulting in early lethality in some cases. In silico and in vitro assays showed that the mutations impaired NKA-pump activity, consistent with severe loss of function [1]. Additionally, Atp1a2-related epileptic encephalopathy and movement disorder patients had severe developmental delay, intellectual disability, drug-resistant epilepsy, severe movement disorder, and recurrent status epilepticus. All had pathogenic ATP1A2 variants, and treatment with antiseizure medication was generally ineffective, but memantine showed moderate improvement [2]. In Atp1a2 knockout mice studies, male heterozygous mice consumed more alcohol than wild-type mice, and there were sex-dependent effects on alcohol-related behaviors, suggesting Atp1a2 contributes modestly to alcohol-related behaviors [5].

In conclusion, Atp1a2 is essential for maintaining Na⁺ and K⁺ gradients, which is vital for neuronal functions. Research on Atp1a2, especially through gene knockout mouse models, has revealed its role in various neurological conditions such as familial hemiplegic migraine, epileptic encephalopathies, and its modest contribution to alcohol-related behaviors. These findings help in understanding the underlying mechanisms of these diseases and potentially developing targeted treatments.