{"doi":"10.1073/pnas.2317769121","title":"Pathogenic gating pore current conducted by autism-related mutations in the Na <sub>V</sub> 1.2 brain sodium channel","abstract":"Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ /K V 7 potassium channel cause gating pore currents (I gp ) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A /Na V 1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of Na V 1.2 caused I gp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective I gp . These potentially pathogenic I gp were exacerbated by the absence of the extracellular Mg 2+ and Ca 2+ . In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward I gp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":428534,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227180,"name":"Brian N. Lundstrom","orcid":"0000-0002-5310-5549","position":1,"is_corresponding":false},{"id":291395,"name":"Jin Li","orcid":"0009-0001-4479-9868","position":2,"is_corresponding":false},{"id":262515,"name":"Larry S. Zweifel","orcid":"0000-0003-3465-5331","position":3,"is_corresponding":false},{"id":299385,"name":"William A. Catterall","orcid":"0000-0001-5509-3580","position":4,"is_corresponding":false},{"id":299384,"name":"Tamer M. Gamal El-Din","orcid":"0000-0002-7406-7393","position":5,"is_corresponding":false},{"id":628342,"name":"Ahmed Eltokhi","orcid":"0000-0001-9067-5017","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:59:02.165535Z","pmid":"38564633","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":[]}