{"doi":"10.1073/pnas.2113675119","title":"An epilepsy-associated K <sub>V</sub> 1.2 charge-transfer-center mutation impairs K <sub>V</sub> 1.2 and K <sub>V</sub> 1.4 trafficking","abstract":"We report on a heterozygous KCNA2 variant in a child with epilepsy. KCNA2 encodes KV1.2 subunits, which form homotetrameric potassium channels and participate in heterotetrameric channel complexes with other KV1-family subunits, regulating neuronal excitability. The mutation causes substitution F233S at the KV1.2 charge transfer center of the voltage-sensing domain. Immunocytochemical trafficking assays showed that KV1.2(F233S) subunits are trafficking deficient and reduce the surface expression of wild-type KV1.2 and KV1.4: a dominant-negative phenotype extending beyond KCNA2, likely profoundly perturbing electrical signaling. Yet some KV1.2(F233S) trafficking was rescued by wild-type KV1.2 and KV1.4 subunits, likely in permissible heterotetrameric stoichiometries: electrophysiological studies utilizing applied transcriptomics and concatemer constructs support that up to one or two KV1.2(F233S) subunits can participate in trafficking-capable heterotetramers with wild-type KV1.2 or KV1.4, respectively, and that both early and late events along the biosynthesis and secretion pathway impair trafficking. These studies suggested that F233S causes a depolarizing shift of ∼48 mV on KV1.2 voltage dependence. Optical tracking of the KV1.2(F233S) voltage-sensing domain (rescued by wild-type KV1.2 or KV1.4) revealed that it operates with modestly perturbed voltage dependence and retains pore coupling, evidenced by off-charge immobilization. The equivalent mutation in the Shaker K+ channel (F290S) was reported to modestly affect trafficking and strongly affect function: an ∼80-mV depolarizing shift, disrupted voltage sensor activation and pore coupling. Our work exposes the multigenic, molecular etiology of a variant associated with epilepsy and reveals that charge-transfer-center disruption has different effects in KV1.2 and Shaker, the archetypes for potassium channel structure and function.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":250464,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"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":892610,"name":"S. Lindström","orcid":"0000-0001-7952-8120","position":1,"is_corresponding":false},{"id":892611,"name":"Maki Kaneko","orcid":"0000-0002-2489-6185","position":2,"is_corresponding":false},{"id":892612,"name":"Kaiqian Wang","orcid":"0000-0002-6315-8732","position":3,"is_corresponding":false},{"id":892613,"name":"Teresa Minguez","orcid":"0000-0001-8049-3869","position":4,"is_corresponding":false},{"id":689111,"name":"Marina Angelini","orcid":"0000-0003-4621-3784","position":5,"is_corresponding":false},{"id":690007,"name":"Federica Steccanella","orcid":null,"position":6,"is_corresponding":false},{"id":892614,"name":"Deborah Holder","orcid":"0000-0001-5532-4764","position":7,"is_corresponding":false},{"id":404852,"name":"Michela Ottolia","orcid":"0000-0002-5114-8887","position":8,"is_corresponding":false},{"id":444321,"name":"Riccardo Olcese","orcid":"0000-0003-4225-9814","position":9,"is_corresponding":false},{"id":725447,"name":"Antonios Pantazis","orcid":"0000-0002-6467-1327","position":10,"is_corresponding":false},{"id":892609,"name":"Michelle Nilsson","orcid":"0000-0002-0891-7732","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"35439054","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":[]}