{"doi":"10.3389/fnmol.2022.892820","title":"Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine","abstract":"Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, CACNA1A , SCN1A , and ATP1A2 , have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the CACNA1I gene encoding the T-type calcium channel Cav3.3. Burden testing of CACNA1I variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, P = 0.00005) and the UK Biobank (OR = 2.32, P = 0.0004) databases. Dysfunction in T-type calcium channels, including Cav3.3, has been implicated in a range of neurological conditions, suggesting a potential role in HM. Using patch-clamp electrophysiology, we compared the biophysical properties of five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, and p.Q1158H) to wild-type (WT) channels expressed in HEK293T cells. We observed numerous functional alterations across the channels with Cav3.3-Q1158H showing the greatest differences compared to WT channels, including reduced current density, right-shifted voltage dependence of activation and inactivation, and slower current kinetics. Interestingly, we also found significant differences in the conductance properties exhibited by the Cav3.3-R307H and -Q1158H variants compared to WT channels under conditions of acidosis and alkalosis. In light of these data, we suggest that rare variants in CACNA1I may contribute to HM etiology.","journal":"Frontiers in Molecular Neuroscience","year":2022,"id":268786,"datarank":0.4493598410330987,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.0,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9603,"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":931526,"name":"Claire D. Blayney","orcid":null,"position":1,"is_corresponding":false},{"id":930981,"name":"Heidi G. Sutherland","orcid":"0000-0002-8512-1498","position":2,"is_corresponding":false},{"id":930982,"name":"Robert A. Smith","orcid":"0000-0003-4825-2461","position":3,"is_corresponding":false},{"id":930983,"name":"Rod A. Lea","orcid":"0000-0002-1148-5862","position":4,"is_corresponding":false},{"id":931527,"name":"Kim Ngan Thi Tran","orcid":null,"position":5,"is_corresponding":false},{"id":930984,"name":"Omar Ibrahim","orcid":"0000-0003-2495-9286","position":6,"is_corresponding":false},{"id":930985,"name":"Jeffrey R. McArthur","orcid":"0000-0002-2546-7913","position":7,"is_corresponding":false},{"id":653857,"name":"Larisa M. Haupt","orcid":"0000-0002-7735-8110","position":8,"is_corresponding":false},{"id":294839,"name":"M. Zameel Cader","orcid":"0000-0002-6952-406X","position":9,"is_corresponding":false},{"id":773513,"name":"Rocio K. Finol‐Urdaneta","orcid":"0000-0003-2157-4532","position":10,"is_corresponding":false},{"id":930986,"name":"David J. Adams","orcid":"0000-0002-7030-2288","position":11,"is_corresponding":false},{"id":294849,"name":"Lyn R. Griffiths","orcid":"0000-0002-6774-5475","position":12,"is_corresponding":false},{"id":930980,"name":"Neven Maksemous","orcid":"0000-0002-4891-4333","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:27:14.088663Z","pmid":"35928792","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":[]}