{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:11:46Z","timestamp":1792026706047,"version":"4.4.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1122387"],"award-info":[{"award-number":["APP1122387"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003965","name":"Migraine Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003965","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022957","name":"International Australian Studies Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020111","name":"Therapeutic Innovation Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020111","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Centre of Medical System Biology (CMSB) in the framework of the Netherlands Genomics Initiative","award":["050-060-409"],"award-info":[{"award-number":["050-060-409"]}]},{"name":"The European Community (EC) FP7-EUROHEADPAIN","award":["602633"],"award-info":[{"award-number":["602633"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract\n<\/jats:title><jats:p>Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel \u03b11A subunit gene <jats:italic>CACNA1A<\/jats:italic> have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the \u201c<jats:italic>CACNA1x<\/jats:italic> gene family\u201d. Whole exome sequencing data of an Australian cohort of unrelated HM patients (<jats:italic>n<\/jats:italic>\u2009=\u2009184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in <jats:italic>CACNA1x<\/jats:italic> genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in <jats:italic>CACNA1E<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20091.3\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>), <jats:italic>CACNA1H<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009&lt;\u20092.2\u2009\u00d7\u200910<jats:sup>\u221216<\/jats:sup>) and <jats:italic>CACNA1I<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009&lt;\u20092.2\u2009\u00d7\u200910<jats:sup>\u221216<\/jats:sup>). There was also a significant burden of subjects with missense variants in <jats:italic>CACNA1E<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20096.2\u2009\u00d7\u200910<jats:sup>\u22123<\/jats:sup>), <jats:italic>CACNA1H<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009&lt;\u20092.2\u2009\u00d7\u200910<jats:sup>\u221216<\/jats:sup>) and <jats:italic>CACNA1I<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009&lt;\u20092.2\u2009\u00d7\u200910<jats:sup>\u221216<\/jats:sup>). Both the number of variants and number of subjects were replicated for <jats:italic>CACNA1H<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20093.5\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>; <jats:italic>p<\/jats:italic>\u2009=\u20090.012) and <jats:italic>CACNA1I<\/jats:italic> (<jats:italic>p<\/jats:italic>\u2009=\u20090.019, <jats:italic>p<\/jats:italic>\u2009=\u20090.044), respectively, in a Dutch clinical HM cohort (<jats:italic>n<\/jats:italic>\u2009=\u200932), albeit that <jats:italic>CACNA1I<\/jats:italic> did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in <jats:italic>CACNA1H<\/jats:italic> and <jats:italic>CACNA1I<\/jats:italic> may contribute to the risk of disease.<\/jats:p>","DOI":"10.1007\/s12035-023-03255-5","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T06:06:05Z","timestamp":1676613965000},"page":"3034-3043","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes"],"prefix":"10.1007","volume":"60","author":[{"given":"Neven","family":"Maksemous","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aster V. E.","family":"Harder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisanne S.","family":"Vijfhuizen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Sutherland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Pelzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"de Boer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela M.","family":"Terwindt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney A.","family":"Lea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arn M. J. M.","family":"van den Maagdenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-5475","authenticated-orcid":false,"given":"Lyn R.","family":"Griffiths","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"3255_CR1","doi-asserted-by":"publisher","unstructured":"(2018) Headache Classification Committee of the International Headache Society (IHS) The international classification of headache disorders, 3rd edition. Cephalalgia 38:1\u2013211. https:\/\/doi.org\/10.1177\/0333102417738202","DOI":"10.1177\/0333102417738202"},{"key":"3255_CR2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1056\/NEJM200107053450103","volume":"345","author":"A Ducros","year":"2001","unstructured":"Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E et al (2001) The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 345:17\u201324. https:\/\/doi.org\/10.1056\/NEJM200107053450103","journal-title":"N Engl J Med"},{"key":"3255_CR3","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/S1474-4422(11)70048-5","volume":"10","author":"MB Russell","year":"2011","unstructured":"Russell MB, Ducros A (2011) Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol 10:457\u2013470. https:\/\/doi.org\/10.1016\/S1474-4422(11)70048-5","journal-title":"Lancet Neurol"},{"key":"3255_CR4","doi-asserted-by":"publisher","first-page":"e575","DOI":"10.1212\/WNL.0000000000004966","volume":"90","author":"N Pelzer","year":"2018","unstructured":"Pelzer N, Haan J, Stam AH, Vijfhuizen LS, Koelewijn SC, Smagge A, de Vries B, Ferrari MD et al (2018) Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation. Neurology 90:e575\u2013e582. https:\/\/doi.org\/10.1212\/WNL.0000000000004966","journal-title":"Neurology"},{"key":"3255_CR5","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/s0092-8674(00)81373-2","volume":"87","author":"RA Ophoff","year":"1996","unstructured":"Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543\u2013552. https:\/\/doi.org\/10.1016\/s0092-8674(00)81373-2","journal-title":"Cell"},{"key":"3255_CR6","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/S0140-6736(05)66786-4","volume":"366","author":"M Dichgans","year":"2005","unstructured":"Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J et al (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366:371\u2013377. https:\/\/doi.org\/10.1016\/S0140-6736(05)66786-4","journal-title":"Lancet"},{"key":"3255_CR7","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/ng1081","volume":"33","author":"M De Fusco","year":"2003","unstructured":"De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P et al (2003) Haploinsufficiency of ATP1A2 encoding the Na+\/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33:192\u2013196. https:\/\/doi.org\/10.1038\/ng1081","journal-title":"Nat Genet"},{"key":"3255_CR8","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1177\/0333102418761041","volume":"38","author":"ME Hiekkala","year":"2018","unstructured":"Hiekkala ME, Vuola P, Artto V, Happola P, Happola E, Vepsalainen S, Cuenca-Leon E, Lal D et al (2018) The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: a clinical and genetic study in Finnish migraine families. Cephalalgia 38:1849\u20131863. https:\/\/doi.org\/10.1177\/0333102418761041","journal-title":"Cephalalgia"},{"key":"3255_CR9","doi-asserted-by":"publisher","unstructured":"Sutherland HG, Maksemous N, Albury CL, Ibrahim O, Smith RA, Lea RA, Haupt LM, Jenkins B et al (2020) Comprehensive exonic sequencing of hemiplegic migraine-related genes in a cohort of suspected probands identifies known and potential pathogenic variants. Cells 9. https:\/\/doi.org\/10.3390\/cells9112368","DOI":"10.3390\/cells9112368"},{"key":"3255_CR10","doi-asserted-by":"publisher","first-page":"e51","DOI":"10.1212\/WNL.0000000000012947","volume":"98","author":"F Riant","year":"2022","unstructured":"Riant F, Roos C, Roubertie A, Barbance C, Hadjadj J, Auvin S, Baille G, Beltramone M et al (2022) Hemiplegic migraine associated with PRRT2 variations: a clinical and genetic study. Neurology 98:e51\u2013e61. https:\/\/doi.org\/10.1212\/WNL.0000000000012947","journal-title":"Neurology"},{"key":"3255_CR11","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.celrep.2016.03.005","volume":"15","author":"P Valente","year":"2016","unstructured":"Valente P, Castroflorio E, Rossi P, Fadda M, Sterlini B, Cervigni RI, Prestigio C, Giovedi S et al (2016) PRRT2 is a key component of the Ca(2+)-dependent neurotransmitter release machinery. Cell Rep 15:117\u2013131. https:\/\/doi.org\/10.1016\/j.celrep.2016.03.005","journal-title":"Cell Rep"},{"key":"3255_CR12","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1212\/WNL.0000000000000590","volume":"83","author":"N Pelzer","year":"2014","unstructured":"Pelzer N, de Vries B, Kamphorst JT, Vijfhuizen LS, Ferrari MD, Haan J, van den Maagdenberg AM, Terwindt GM (2014) PRRT2 and hemiplegic migraine: a complex association. Neurology 83:288\u2013290. https:\/\/doi.org\/10.1212\/WNL.0000000000000590","journal-title":"Neurology"},{"key":"3255_CR13","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.neuron.2018.04.014","volume":"98","author":"P Gormley","year":"2018","unstructured":"Gormley P, Kurki M, Kurki MI, Hiekkala M, Hiekkala ME, Veerapen K, H\u00e4pp\u00f6l\u00e4 P, Mitchell AA et al (2018) Common variant burden contributes to the familial aggregation of migraine in 1,589 families. Neuron 98:743-753.e4. https:\/\/doi.org\/10.1016\/j.neuron.2018.04.014","journal-title":"Neuron"},{"key":"3255_CR14","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/gm131","volume":"2","author":"NR Wray","year":"2010","unstructured":"Wray NR, Goddard ME (2010) Multi-locus models of genetic risk of disease. Genome Med 2:10. https:\/\/doi.org\/10.1186\/gm131","journal-title":"Genome Med"},{"key":"3255_CR15","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1038\/ng.2437","volume":"44","author":"J Gudmundsson","year":"2012","unstructured":"Gudmundsson J, Sulem P, Gudbjartsson DF, Masson G, Agnarsson BA, Benediktsdottir KR, Sigurdsson A, Magnusson OT et al (2012) A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet 44:1326\u20131329. https:\/\/doi.org\/10.1038\/ng.2437","journal-title":"Nat Genet"},{"key":"3255_CR16","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1038\/ng.952","volume":"43","author":"MA Rivas","year":"2011","unstructured":"Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, Boucher G, Ripke S et al (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066\u20131073. https:\/\/doi.org\/10.1038\/ng.952","journal-title":"Nat Genet"},{"key":"3255_CR17","doi-asserted-by":"publisher","first-page":"R16","DOI":"10.1093\/hmg\/ddt376","volume":"22","author":"K Panoutsopoulou","year":"2013","unstructured":"Panoutsopoulou K, Tachmazidou I, Zeggini E (2013) In search of low-frequency and rare variants affecting complex traits. Hum Mol Genet 22:R16-21. https:\/\/doi.org\/10.1093\/hmg\/ddt376","journal-title":"Hum Mol Genet"},{"key":"3255_CR18","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/S1474-4422(14)70220-0","volume":"14","author":"MDP Ferrari","year":"2015","unstructured":"Ferrari MDP, Klever RRM, Terwindt GMMD, Ayata CMD, van den Maagdenberg AMJMP (2015) Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol 14:65\u201380. https:\/\/doi.org\/10.1016\/S1474-4422(14)70220-0","journal-title":"Lancet Neurol"},{"key":"3255_CR19","doi-asserted-by":"publisher","first-page":"6403","DOI":"10.1523\/JNEUROSCI.15-10-06403.1995","volume":"15","author":"RE Westenbroek","year":"1995","unstructured":"Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TV, Snutch TP, Catterall WA (1995) Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci 15:6403\u20136418","journal-title":"J Neurosci"},{"key":"3255_CR20","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/s0143-4160(98)90055-0","volume":"24","author":"WA Catterall","year":"1998","unstructured":"Catterall WA (1998) Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 24:307\u2013323. https:\/\/doi.org\/10.1016\/s0143-4160(98)90055-0","journal-title":"Cell Calcium"},{"key":"3255_CR21","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/0166-2236(95)80030-6","volume":"18","author":"K Dunlap","year":"1995","unstructured":"Dunlap K, Luebke JI, Turner TJ (1995) Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci 18:89\u201398","journal-title":"Trends Neurosci"},{"key":"3255_CR22","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1152\/physrev.00018.2002","volume":"83","author":"E Perez-Reyes","year":"2003","unstructured":"Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117\u2013161. https:\/\/doi.org\/10.1152\/physrev.00018.2002","journal-title":"Physiol Rev"},{"key":"3255_CR23","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/nrn3311","volume":"13","author":"AC Dolphin","year":"2012","unstructured":"Dolphin AC (2012) Calcium channel auxiliary \u03b12\u03b4 and \u03b2 subunits: trafficking and one step beyond. Nat Rev Neurosci 13:542\u2013555. https:\/\/doi.org\/10.1038\/nrn3311","journal-title":"Nat Rev Neurosci"},{"key":"3255_CR24","doi-asserted-by":"publisher","first-page":"e1005492","DOI":"10.1371\/journal.pgen.1005492","volume":"11","author":"S Petrovski","year":"2015","unstructured":"Petrovski S, Gussow AB, Wang Q, Halvorsen M, Han Y, Weir WH, Allen AS, Goldstein DB (2015) The intolerance of regulatory sequence to genetic variation predicts gene dosage sensitivity. PLoS Genet 11:e1005492. https:\/\/doi.org\/10.1371\/journal.pgen.1005492","journal-title":"PLoS Genet"},{"key":"3255_CR25","doi-asserted-by":"publisher","unstructured":"(2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580\u20135. https:\/\/doi.org\/10.1038\/ng.2653","DOI":"10.1038\/ng.2653"},{"key":"3255_CR26","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1111\/head.13107","volume":"57","author":"A Ambrosini","year":"2017","unstructured":"Ambrosini A, D\u2019Onofrio M, Buzzi MG, Arisi I, Grieco GS, Pierelli F, Santorelli FM, Schoenen J (2017) Possible involvement of the CACNA1E gene in migraine: a search for single nucleotide polymorphism in different clinical phenotypes. Headache 57:1136\u20131144. https:\/\/doi.org\/10.1111\/head.13107","journal-title":"Headache"},{"key":"3255_CR27","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1177\/0333102412463494","volume":"33","author":"M Kurtuncu","year":"2013","unstructured":"Kurtuncu M, Kaya D, Zuliani L, Erdag E, Icoz S, Ugurel E, Cavus F, Aysit N et al (2013) CACNA1H antibodies associated with headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL). Cephalalgia Int J Headache 33:123\u2013129. https:\/\/doi.org\/10.1177\/0333102412463494","journal-title":"Cephalalgia Int J Headache"},{"key":"3255_CR28","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1002\/humu.24017","volume":"41","author":"JD Calhoun","year":"2020","unstructured":"Calhoun JD, Huffman AM, Bellinski I, Kinsley L, Bachman E, Gerard E, Kearney JA, Carvill GL (2020) CACNA1H variants are not a cause of monogenic epilepsy. Hum Mutat 41:1138\u20131144. https:\/\/doi.org\/10.1002\/humu.24017","journal-title":"Hum Mutat"},{"key":"3255_CR29","doi-asserted-by":"publisher","first-page":"2945","DOI":"10.1093\/brain\/awaa242","volume":"143","author":"AH Rasmussen","year":"2020","unstructured":"Rasmussen AH, Kogelman LJA, Kristensen DM, Chalmer MA, Olesen J, Hansen TF (2020) Functional gene networks reveal distinct mechanisms segregating in migraine families. Brain J Neurol 143:2945\u20132956. https:\/\/doi.org\/10.1093\/brain\/awaa242","journal-title":"Brain J Neurol"},{"key":"3255_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00990-0","author":"H Hautakangas","year":"2022","unstructured":"Hautakangas H, Winsvold BS, Ruotsalainen SE, Bjornsdottir G, Harder AVE, Kogelman LJA, Thomas LF, Noordam R et al (2022) Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat Genet. https:\/\/doi.org\/10.1038\/s41588-021-00990-0","journal-title":"Nat Genet"},{"key":"3255_CR31","doi-asserted-by":"publisher","first-page":"251581631988163","DOI":"10.1177\/2515816319881630","volume":"2","author":"N Maksemous","year":"2019","unstructured":"Maksemous N, Smith RA, Sutherland HG, Maher BH, Ibrahim O, Nicholson GA, Carpenter EP, Lea RA et al (2019) Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine. Cephalalgia Rep 2:2515816319881630. https:\/\/doi.org\/10.1177\/2515816319881630","journal-title":"Cephalalgia Rep"},{"key":"3255_CR32","doi-asserted-by":"publisher","unstructured":"(2013) The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:629\u2013808. https:\/\/doi.org\/10.1177\/0333102413485658","DOI":"10.1177\/0333102413485658"},{"key":"3255_CR33","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","volume":"16","author":"SA Miller","year":"1988","unstructured":"Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215. https:\/\/doi.org\/10.1093\/nar\/16.3.1215","journal-title":"Nucleic Acids Res"},{"key":"3255_CR34","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1093\/brain\/awf132","volume":"125","author":"LL Thomsen","year":"2002","unstructured":"Thomsen LL, Eriksen MK, Roemer SF, Andersen I, Olesen J, Russell MB (2002) A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain 125:1379\u20131391. https:\/\/doi.org\/10.1093\/brain\/awf132","journal-title":"Brain"},{"key":"3255_CR35","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754\u20131760. https:\/\/doi.org\/10.1093\/bioinformatics\/btp324","journal-title":"Bioinformatics"},{"key":"3255_CR36","doi-asserted-by":"publisher","unstructured":"Danecek P, Bonfield JK, Liddle J, Marshall J, Ohan V, Pollard MO, Whitwham A, Keane T et al (2021) Twelve years of SAMtools and BCFtools. Gigascience 10. https:\/\/doi.org\/10.1093\/gigascience\/giab008","DOI":"10.1093\/gigascience\/giab008"},{"key":"3255_CR37","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4161\/fly.19695","volume":"6","author":"P Cingolani","year":"2012","unstructured":"Cingolani P, Platts A, le Wang L, Coon M, Nguyen T, Wang L, Land SJ, Lu X et al (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6:80\u201392. https:\/\/doi.org\/10.4161\/fly.19695","journal-title":"Fly (Austin)"},{"key":"3255_CR38","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The Ensembl variant effect predictor. Genome Biol 17:122. https:\/\/doi.org\/10.1186\/s13059-016-0974-4","journal-title":"Genome Biol"},{"key":"3255_CR39","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.ajhg.2018.08.016","volume":"103","author":"MH Guo","year":"2018","unstructured":"Guo MH, Plummer L, Chan YM, Hirschhorn JN, Lippincott MF (2018) Burden testing of rare variants identified through exome sequencing via publicly available control data. Am J Hum Genet 103:522\u2013534. https:\/\/doi.org\/10.1016\/j.ajhg.2018.08.016","journal-title":"Am J Hum Genet"},{"key":"3255_CR40","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1136\/jech.46.4.443","volume":"46","author":"BK Rasmussen","year":"1992","unstructured":"Rasmussen BK, Jensen R, Olesen J (1992) Impact of headache on sickness absence and utilisation of medical services: a Danish population study. J Epidemiol Community Health 46:443\u2013446. https:\/\/doi.org\/10.1136\/jech.46.4.443","journal-title":"J Epidemiol Community Health"},{"key":"3255_CR41","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/s0896-6273(00)81057-0","volume":"25","author":"EA Ertel","year":"2000","unstructured":"Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, Schwartz A, Snutch TP et al (2000) Nomenclature of voltage-gated calcium channels. Neuron 25:533\u2013535. https:\/\/doi.org\/10.1016\/s0896-6273(00)81057-0","journal-title":"Neuron"},{"key":"3255_CR42","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1113\/jphysiol.2001.013269","volume":"540","author":"J Chemin","year":"2002","unstructured":"Chemin J, Monteil A, Perez-Reyes E, Bourinet E, Nargeot J, Lory P (2002) Specific contribution of human T-type calcium channel isotypes (alpha(1G), alpha(1H) and alpha(1I)) to neuronal excitability. J Physiol 540:3\u201314. https:\/\/doi.org\/10.1113\/jphysiol.2001.013269","journal-title":"J Physiol"},{"key":"3255_CR43","doi-asserted-by":"publisher","first-page":"475","DOI":"10.4161\/chan.4.6.14106","volume":"4","author":"SM Cain","year":"2010","unstructured":"Cain SM, Snutch TP (2010) Contributions of T-type calcium channel isoforms to neuronal firing. Channels (Austin Tex) 4:475\u2013482. https:\/\/doi.org\/10.4161\/chan.4.6.14106","journal-title":"Channels (Austin Tex)"},{"key":"3255_CR44","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1038\/nn.2757","volume":"14","author":"Z Huang","year":"2011","unstructured":"Huang Z, Lujan R, Kadurin I, Uebele VN, Renger JJ, Dolphin AC, Shah MM (2011) Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses. Nat Neurosci 14:478\u2013486. https:\/\/doi.org\/10.1038\/nn.2757","journal-title":"Nat Neurosci"},{"key":"3255_CR45","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/s0896-6273(01)00454-8","volume":"32","author":"ZH Pan","year":"2001","unstructured":"Pan ZH, Hu HJ, Perring P, Andrade R (2001) T-type Ca(2+) channels mediate neurotransmitter release in retinal bipolar cells. Neuron 32:89\u201398. https:\/\/doi.org\/10.1016\/s0896-6273(01)00454-8","journal-title":"Neuron"},{"key":"3255_CR46","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1016\/j.bbamem.2012.07.031","volume":"1828","author":"N Weiss","year":"2013","unstructured":"Weiss N, Zamponi GW (2013) Control of low-threshold exocytosis by T-type calcium channels. Biochim Biophys Acta 1828:1579\u20131586. https:\/\/doi.org\/10.1016\/j.bbamem.2012.07.031","journal-title":"Biochim Biophys Acta"},{"key":"3255_CR47","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1124\/pr.114.009654","volume":"67","author":"GW Zamponi","year":"2015","unstructured":"Zamponi GW, Striessnig J, Koschak A, Dolphin AC (2015) The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 67:821\u2013870. https:\/\/doi.org\/10.1124\/pr.114.009654","journal-title":"Pharmacol Rev"},{"key":"3255_CR48","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1111\/j.1601-183X.2006.00268.x","volume":"6","author":"S Choi","year":"2007","unstructured":"Choi S, Na HS, Kim J, Lee J, Lee S, Kim D, Park J, Chen CC et al (2007) Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels. Genes Brain Behav 6:425\u2013431. https:\/\/doi.org\/10.1111\/j.1601-183X.2006.00268.x","journal-title":"Genes Brain Behav"},{"key":"3255_CR49","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/sj.emboj.7600515","volume":"24","author":"E Bourinet","year":"2005","unstructured":"Bourinet E, Alloui A, Monteil A, Barrere C, Couette B, Poirot O, Pages A, McRory J et al (2005) Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. EMBO J 24:315\u2013324. https:\/\/doi.org\/10.1038\/sj.emboj.7600515","journal-title":"EMBO J"},{"key":"3255_CR50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/jmedgenet-2019-106163","volume":"57","author":"N Weiss","year":"2020","unstructured":"Weiss N, Zamponi GW (2020) Genetic T-type calcium channelopathies. J Med Genet 57:1\u201310. https:\/\/doi.org\/10.1136\/jmedgenet-2019-106163","journal-title":"J Med Genet"},{"key":"3255_CR51","doi-asserted-by":"publisher","unstructured":"Gangarossa G, Laffray S, Bourinet E, Valjent E (2014) T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants. 8. https:\/\/doi.org\/10.3389\/fnbeh.2014.00092","DOI":"10.3389\/fnbeh.2014.00092"},{"key":"3255_CR52","doi-asserted-by":"publisher","first-page":"13823","DOI":"10.1073\/pnas.1105115108","volume":"108","author":"S Astori","year":"2011","unstructured":"Astori S, Wimmer RD, Prosser HM, Corti C, Corsi M, Liaudet N, Volterra A, Franken P et al (2011) The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus. Proc Natl Acad Sci USA 108:13823\u201313828. https:\/\/doi.org\/10.1073\/pnas.1105115108","journal-title":"Proc Natl Acad Sci USA"},{"key":"3255_CR53","doi-asserted-by":"publisher","first-page":"22085","DOI":"10.1074\/jbc.M603316200","volume":"281","author":"I Splawski","year":"2006","unstructured":"Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT (2006) CACNA1H Mutations in autism spectrum disorders*. J Biol Chem 281:22085\u201322091. https:\/\/doi.org\/10.1074\/jbc.M603316200","journal-title":"J Biol Chem"},{"key":"3255_CR54","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1080\/19336950.2019.1614415","volume":"13","author":"MT Carter","year":"2019","unstructured":"Carter MT, McMillan HJ, Tomin A, Weiss N (2019) Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy. Channels (Austin) 13:153\u2013161. https:\/\/doi.org\/10.1080\/19336950.2019.1614415","journal-title":"Channels (Austin)"},{"key":"3255_CR55","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.cell.2013.06.049","volume":"154","author":"S Gulsuner","year":"2013","unstructured":"Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, Rippey C, Shahin H et al (2013) Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154:518\u2013529. https:\/\/doi.org\/10.1016\/j.cell.2013.06.049","journal-title":"Cell"},{"key":"3255_CR56","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1093\/brain\/awab101","volume":"144","author":"Y El Ghaleb","year":"2021","unstructured":"El Ghaleb Y, Schneeberger PE, Fernandez-Quintero ML, Geisler SM, Pelizzari S, Polstra AM, van Hagen JM, Denecke J et al (2021) CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders. Brain 144:2092\u20132106. https:\/\/doi.org\/10.1093\/brain\/awab101","journal-title":"Brain"},{"key":"3255_CR57","doi-asserted-by":"publisher","first-page":"892820","DOI":"10.3389\/fnmol.2022.892820","volume":"15","author":"N Maksemous","year":"2022","unstructured":"Maksemous N, Blayney CD, Sutherland HG, Smith RA, Lea RA, Tran KN, Ibrahim O, McArthur JR et al (2022) Investigation of CACNA1I Cav3.3 dysfunction in hemiplegic migraine. Front Mol Neurosci 15:892820. https:\/\/doi.org\/10.3389\/fnmol.2022.892820","journal-title":"Front Mol Neurosci"},{"key":"3255_CR58","doi-asserted-by":"publisher","first-page":"3567","DOI":"10.1093\/brain\/awv310","volume":"138","author":"AR Gardiner","year":"2015","unstructured":"Gardiner AR, Jaffer F, Dale RC, Labrum R, Erro R, Meyer E, Xiromerisiou G, Stamelou M et al (2015) The clinical and genetic heterogeneity of paroxysmal dyskinesias. Brain 138:3567\u20133580. https:\/\/doi.org\/10.1093\/brain\/awv310","journal-title":"Brain"},{"key":"3255_CR59","doi-asserted-by":"publisher","first-page":"15963","DOI":"10.1073\/pnas.1008705107","volume":"107","author":"M Suzuki","year":"2010","unstructured":"Suzuki M, Van Paesschen W, Stalmans I, Horita S, Yamada H, Bergmans BA, Legius E, Riant F et al (2010) Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine. Proc Natl Acad Sci USA 107:15963\u201315968. https:\/\/doi.org\/10.1073\/pnas.1008705107","journal-title":"Proc Natl Acad Sci USA"},{"key":"3255_CR60","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1212\/01.wnl.0000172638.58172.5a","volume":"65","author":"JC Jen","year":"2005","unstructured":"Jen JC, Wan J, Palos TP, Howard BD, Baloh RW (2005) Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 65:529\u2013534. https:\/\/doi.org\/10.1212\/01.wnl.0000172638.58172.5a","journal-title":"Neurology"},{"key":"3255_CR61","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1177\/0333102414532379","volume":"35","author":"CM Weller","year":"2015","unstructured":"Weller CM, Leen WG, Neville BG, Duncan JS, de Vries B, Geilenkirchen MA, Haan J, Kamsteeg EJ et al (2015) A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood. Cephalalgia 35:10\u201315. https:\/\/doi.org\/10.1177\/0333102414532379","journal-title":"Cephalalgia"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-023-03255-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-023-03255-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-023-03255-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T09:11:15Z","timestamp":1682154675000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-023-03255-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,14]]},"references-count":61,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["3255"],"URL":"https:\/\/doi.org\/10.1007\/s12035-023-03255-5","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,14]]},"assertion":[{"value":"20 November 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2023","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Missing Open Access funding information has been added in the Funding Note.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Human Research Ethics Committee of the Queensland University of Technology (approval number: 1800000611) and by the Medical Ethics Committee of LUMC.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Appropriate consents for the patient cohort are already in place.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"GMT reports consultancy support from Novartis, Allergan\/Abbvie, Lilly, and Teva, Lundbeck and independent support from Dutch Research Council, the Dutch Heart & Brain Foundations, IRRF and Dioraphte. AMJMvdM reports research support from Praxis Precision Medicine and Schedule 1 Therapeutics and consultancy support from AbbVie. LRG reports recent consultancy support from Teva and research support from the Australian National Health and Medical Research Council and the US Migraine Research Foundation. IdB reports independent support from the International Retinal Research Foundation and Dutch Heart Foundation. AVEH, LSV, OI, NP, NM, HS and RAL declare no conflict of interest.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}