{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:57:38Z","timestamp":1789516658986,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Migraine is a prevalent neurological disorder that affects over 1 billion individuals worldwide. The pathogenesis of migraine remains incompletely understood, though evidence suggests a multifactorial etiology involving genetic factors. The CACNA1A gene has been implicated in rare forms of Familial Hemiplegic Migraine (FHM). This study aimed to investigate the role of CACNA1A variants in individuals with and without a family history of migraine. We genotyped 150 subjects (100 migraine patients: 50 with migraine without aura (MO), 50 with migraine with aura (MA) and 50 controls) for six CACNA1A variants using Sanger sequencing. Statistical analyses were performed in Statistica (p &lt; 0.05). The CADD v1.7 model was used to assess the potential pathogenicity of novel variants. Three variants described in databases (rs10405121, rs894252513, and rs1012663275) and three novel variants (ch19:13228374 G &gt; C, ch19:13228428 G &gt; C, and ch19:13228348 A &gt; T) were identified. The rs10405121 variant was associated with both migraine types, with the homozygous AA genotype exclusively found in familial cases. Abnormal genotype of rs894252513 and rs1012663275 were detected only in familial cases with MO. The novel variants were observed exclusively in patients with a family history of migraine, suggesting their potential relevance to inherited migraine pathogenesis. Novel variants may contribute to migraine pathogenesis by altering calcium channel function and lowering the threshold for cortical spreading depression (CSD).<\/jats:p>","DOI":"10.3390\/ijms26168083","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:41:45Z","timestamp":1755848505000},"page":"8083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["CACNA1A Genetic Variants and Their Potential Involvement in Migraine Pathogenesis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5326-6388","authenticated-orcid":false,"given":"Oliwia","family":"Szymanowicz","sequence":"first","affiliation":[{"name":"Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 60-355 Poznan, Poland"},{"name":"Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"S\u0142owikowski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Poszwa","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 60-355 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulyana","family":"Goutor","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 60-355 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Wiszniewska","sequence":"additional","affiliation":[{"name":"Faculty of Health, Care Stanislaw Staszic University of Applied Sciences in Pila, 64-920 Pila, Poland"},{"name":"Department of Neurology, Specialistic Hospital in Pila, 64-920 Pila, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9046-6802","authenticated-orcid":false,"given":"Pawe\u0142 P.","family":"Jagodzi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Kozubski","sequence":"additional","affiliation":[{"name":"Chair and Department of Neurology, Poznan University of Medical Sciences, 60-355 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8241-0403","authenticated-orcid":false,"given":"Jolanta","family":"Dorszewska","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 60-355 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, February 23). Migraine and Other Headache Disorders. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/headache-disorders."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1097\/j.pain.0000000000002275","article-title":"Global, regional, and national burden of migraine in 204 countries and territories, 1990 to 2019","volume":"163","author":"Safiri","year":"2022","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s10072-020-04643-8","article-title":"Gender-related differences in migraine","volume":"41","author":"Allais","year":"2020","journal-title":"Neurol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1185\/0300799039117005","article-title":"Epidemiology and economic impact of migraine","volume":"17","author":"Lipton","year":"2001","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0028-3843(14)60054-2","article-title":"Frequency and clinical characteristics of chronic daily headache in an outpatient clinic setting","volume":"45","author":"Karbowniczek","year":"2011","journal-title":"Neurol. Neurochir. Pol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/0333102417738202","article-title":"Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition","volume":"38","author":"Arnold","year":"2018","journal-title":"Cephalalgia"},{"key":"ref_7","unstructured":"Pescador Ruschel, M.A., and De Jesus, O. (2024). Migraine Headache. StatPearls, StatPearls Publishing."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41582-021-00509-5","article-title":"Diagnosis and management of migraine in ten steps","volume":"17","author":"Eigenbrodt","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.4103\/jfmpc.jfmpc_376_19","article-title":"Factors associated with delayed diagnosis of migraine: A hospital-based cross-sectional study","volume":"8","author":"Rai","year":"2019","journal-title":"J. Family. Med. Prim. Care."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Frimpong-Manson, K., Ortiz, Y.T., McMahon, L.R., and Wilkerson, J.L. (2024). Advances in understanding migraine pathophysiology: A bench to bedside review of research insights and therapeutics. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1355281"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dell\u2019Isola, G.B., Tulli, E., Sica, R., Vinti, V., Mencaroni, E., Di Cara, G., Striano, P., and Verrotti, A. (2021). The Vitamin D Role in Preventing Primary Headache in Adult and Pediatric Population. J. Clin. Med., 10.","DOI":"10.3390\/jcm10245983"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Amiri, P., Kazeminasab, S., Nejadghaderi, S.A., Mohammadinasab, R., Pourfathi, H., Araj-Khodaei, M., Sullman, M.J.M., Kolahi, A.A., and Safiri, S. (2022). Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.800605"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/jcbfm.2010.191","article-title":"Clinical relevance of cortical spreading depression in neurological disorders: Migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury","volume":"31","author":"Lauritzen","year":"2011","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/brain\/117.1.199","article-title":"Pathophysiology of the migraine aura. The spreading depression theory","volume":"117","author":"Lauritzen","year":"1994","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.2174\/1570159X20666220327211156","article-title":"The role of voltage-gated calcium channels in basal ganglia neurodegenerative disorders","volume":"21","author":"Correa","year":"2023","journal-title":"Curr. Neuropharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1111\/j.1476-5381.2012.02069.x","article-title":"P\/Q-type calcium channel modulators","volume":"167","author":"Nimmrich","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1080\/19336950.2021.1900024","article-title":"More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation","volume":"15","author":"Heck","year":"2021","journal-title":"Channels"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s10194-021-01370-z","article-title":"Cortical spreading depression induces propagating activation of the thalamus ventral posteromedial nucleus in awake mice","volume":"23","author":"Fu","year":"2022","journal-title":"J. Headache Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.nurt.2007.01.008","article-title":"Familial hemiplegic migraine","volume":"4","author":"Pietrobon","year":"2007","journal-title":"Neurotherapeutics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1111\/j.1468-2982.2008.01599.x","article-title":"Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients","volume":"28","author":"Thomsen","year":"2008","journal-title":"Cephalalgia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.bbadis.2012.04.008","article-title":"Familial hemiplegic migraine type 1 mutations W1684R and V1696I alter G protein-mediated regulation of Ca(V)2.1 voltage-gated calcium channels","volume":"1822","author":"Sandoval","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/s10194-024-01903-2","article-title":"Cerebral blood flow and arterial responses in migraine: History and future perspectives","volume":"25","author":"Olesen","year":"2024","journal-title":"J. Headache Pain."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/S0896-6273(04)00085-6","article-title":"Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression","volume":"41","author":"Pietrobon","year":"2004","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1111\/j.1468-2982.2009.02015.x","article-title":"History of migraine with aura and cortical spreading depression from 1941 and onwards","volume":"30","year":"2010","journal-title":"Cephalalgia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1111\/epi.16316","article-title":"Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome","volume":"60","author":"Jiang","year":"2019","journal-title":"Epilepsia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"142202","DOI":"10.1172\/JCI142202","article-title":"Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model","volume":"131","author":"Auffenberg","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6394","DOI":"10.1523\/JNEUROSCI.20-17-06394.2000","article-title":"The polyglutamine expansion in spinocerebellar ataxia type 6 causes a beta subunit-specific enhanced activation of P\/Q-type calcium channels in Xenopus oocytes","volume":"20","author":"Restituito","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.nurt.2007.01.003","article-title":"Molecular pathogenesis of spinocerebellar ataxia type 6","volume":"4","author":"Kordasiewicz","year":"2007","journal-title":"Neurotherapeutics"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Spekker, E., Nagy-Gr\u00f3cz, G., and V\u00e9csei, L. (2023). Ion channel disturbances in migraine headache: Exploring the potential role of the kynurenine system in the context of the trigeminovascular system. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242316574"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Eren-Ko\u00e7ak, E., and Dalkara, T. (2021). Ion channel dysfunction and neuroinflammation in migraine and depression. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.777607"},{"key":"ref_31","unstructured":"(2025, February 23). National Library of Medicine, Available online: https:\/\/www.ncbi.nlm.nih.gov\/snp\/rs10405121."},{"key":"ref_32","unstructured":"(2025, February 23). National Library of Medicine, Available online: https:\/\/www.ncbi.nlm.nih.gov\/snp\/rs894252513."},{"key":"ref_33","unstructured":"(2025, February 23). National Library of Medicine, Available online: https:\/\/www.ncbi.nlm.nih.gov\/snp\/rs1012663275."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S1474-4422(02)00134-5","article-title":"The genetics of migraine","volume":"1","author":"Ducros","year":"2002","journal-title":"Lancet Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s10194-023-01547-8","article-title":"Genetics of migraine: Where are we now?","volume":"24","author":"Grangeon","year":"2023","journal-title":"J. Headache Pain"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gosalia, H., Karsan, N., and Goadsby, P.J. (2023). Genetic mechanisms of migraine: Insights from monogenic migraine mutations. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612697"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s10194-019-1017-9","article-title":"Advances in genetics of migraine","volume":"20","author":"Sutherland","year":"2019","journal-title":"J. Headache Pain"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Szymanowicz, O., Dru\u017cd\u017c, A., S\u0142owikowski, B., Pawlak, S., Potocka, E., Goutor, U., Konieczny, M., Ciasto\u0144, M., Lewandowska, A., and Jagodzi\u0144ski, P.P. (2024). A Review of the CACNA gene family: Its role in neurological disorders. Diseases, 12.","DOI":"10.3390\/diseases12050090"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41588-021-00990-0","article-title":"Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles","volume":"54","author":"Hautakangas","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1038\/s41588-023-01538-0","article-title":"Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura","volume":"55","author":"Bjornsdottir","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"224","DOI":"10.2174\/1389202921666200415181222","article-title":"Analysis of genetic variants in SCN1A, SCN2A, KCNK18, TRPA1 and STX1A as a possible marker of migraine","volume":"21","author":"Kowalska","year":"2020","journal-title":"Curr. Genomics"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Pikor, D., Hur\u0142a, M., S\u0142owikowski, B., Szymanowicz, O., Poszwa, J., Banaszek, N., Drelichowska, A., Jagodzi\u0144ski, P.P., Kozubski, W., and Dorszewska, J. (2024). Calcium Ions in the Physiology and Pathology of the Central Nervous System. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252313133"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1093\/ajh\/hpw070","article-title":"Associations of variants in the CACNA1A and CACNA1C genes with longitudinal blood pressure changes and hypertension incidence: The GenSalt study","volume":"29","author":"Hu","year":"2016","journal-title":"Am. J. Hypertens."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8083\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:43Z","timestamp":1760034763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":43,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26168083"],"URL":"https:\/\/doi.org\/10.3390\/ijms26168083","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}