{"doi":"10.1093/hmg/ddac087","title":"Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in <i>Scn2a</i> <i>K1422E</i> mice","abstract":"Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.","journal":"Human Molecular Genetics","year":2022,"id":247744,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9469,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":654499,"name":"Nicole A. Hawkins","orcid":null,"position":1,"is_corresponding":false},{"id":814629,"name":"Sunita N. Misra","orcid":"0000-0002-7624-8825","position":2,"is_corresponding":false},{"id":773875,"name":"Alexandra M Huffman","orcid":"0000-0003-1223-1888","position":3,"is_corresponding":false},{"id":814630,"name":"Tyler Thaxton","orcid":"0000-0002-9901-7771","position":4,"is_corresponding":false},{"id":347997,"name":"Christopher H. Thompson","orcid":"0000-0003-3713-630X","position":5,"is_corresponding":false},{"id":347998,"name":"Roy Ben‐Shalom","orcid":"0000-0002-5742-5769","position":6,"is_corresponding":false},{"id":814631,"name":"Andrew D. Nelson","orcid":"0000-0001-8379-3058","position":7,"is_corresponding":false},{"id":585742,"name":"Anna M. Lipkin","orcid":"0000-0001-5887-9044","position":8,"is_corresponding":false},{"id":321394,"name":"Alfred L. George","orcid":"0000-0002-3993-966X","position":9,"is_corresponding":false},{"id":293049,"name":"Kevin J. Bender","orcid":"0000-0001-7084-1532","position":10,"is_corresponding":false},{"id":425626,"name":"Jennifer A. Kearney","orcid":"0000-0003-1726-4769","position":11,"is_corresponding":false},{"id":814628,"name":"Dennis M. Echevarria-Cooper","orcid":"0000-0002-1703-1319","position":0,"is_corresponding":true}],"reference_count":114,"raw_metadata":null,"created_at":"2026-07-19T00:23:57.824223Z","pmid":"35417922","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}