{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T08:02:18Z","timestamp":1775894538865,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,14]]},"group-title":"Genetics","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Timothy syndrome (TS) is a multisystem disorder with autistic-like features, seizures and arrhythmia as the main symptoms. Most TS cases are caused by a\n                  <jats:italic>de novo<\/jats:italic>\n                  single amino acid substitution G406R in the\n                  <jats:italic>CACNA1C<\/jats:italic>\n                  gene that encodes the pore-forming subunit of the voltage-gated L-type calcium channel Ca\n                  <jats:sub>V<\/jats:sub>\n                  1.2. We generated a zebrafish model of TS with a homologous amino acid substitution in the\n                  <jats:italic>cacna1c<\/jats:italic>\n                  -encoded protein. Unlike patients, heterozygous mutants showed only mild impairments with no changes in mortality. However, homozygous mutants showed increased mortality, arrhythmias, neural activity and sensitivity to pentylenetetrazole-induced seizure-like behavior. Mutants also exhibited microcephaly, cerebellar hypotrophy and abnormal development of GABAergic neuron populations, and transcriptomic analysis revealed dysregulated expression of neuropeptide genes (including\n                  <jats:italic>bdnf<\/jats:italic>\n                  and\n                  <jats:italic>vgf<\/jats:italic>\n                  ). Consistent with the idea that Ca\n                  <jats:sub>V<\/jats:sub>\n                  1.2 channels activate during fever, we found that heterozygous larvae manifested arrhythmia and seizure-like behavior when exposed to elevated environmental temperature, and homozygous larvae switched from bradycardia to tachycardia. These data provide a basis for using zebrafish to study the etiology of TS abnormalities and suggest t hat fever may be a particular risk for TS patients.\n                <\/jats:p>","DOI":"10.1101\/2025.03.11.642683","type":"posted-content","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T12:10:11Z","timestamp":1741954211000},"source":"Crossref","is-referenced-by-count":1,"title":["Elevated body temperature exacerbates arrhythmia and seizure-like activity in a zebrafish model of Timothy syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2311-4142","authenticated-orcid":false,"given":"Svetlana A.","family":"Semenova","sequence":"first","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5948-4153","authenticated-orcid":false,"given":"Amir M.","family":"Sams","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3761-0430","authenticated-orcid":false,"given":"Deepthi","family":"Nammi","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4728-2470","authenticated-orcid":false,"given":"Matthew","family":"Menold","sequence":"additional","affiliation":[{"name":"Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gennady","family":"Margolin","sequence":"additional","affiliation":[{"name":"Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9860-7738","authenticated-orcid":false,"given":"Jennifer L.","family":"Sinclair","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katelyn A.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6410-9337","authenticated-orcid":false,"given":"Kerry","family":"Larkin","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney","family":"Kelly","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8599-2031","authenticated-orcid":false,"given":"Andy","family":"Golden","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4838-8641","authenticated-orcid":false,"given":"Benjamin","family":"Feldman","sequence":"additional","affiliation":[{"name":"Zebrafish Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1966-7801","authenticated-orcid":false,"given":"Harold A.","family":"Burgess","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041100282708000_2025.03.11.642683v1.1","doi-asserted-by":"crossref","unstructured":"R. Bauer , K. W. Timothy , A. Golden , Update on the Molecular Genetics of Timothy Syndrome. Front Pediatr 9, 668546 (2021).","DOI":"10.3389\/fped.2021.668546"},{"key":"2026041100282708000_2025.03.11.642683v1.2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51037"},{"key":"2026041100282708000_2025.03.11.642683v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.208116"},{"key":"2026041100282708000_2025.03.11.642683v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1112667108"},{"key":"2026041100282708000_2025.03.11.642683v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/2211-5463.12924"},{"key":"2026041100282708000_2025.03.11.642683v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature22330"},{"key":"2026041100282708000_2025.03.11.642683v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.11.011"},{"key":"2026041100282708000_2025.03.11.642683v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07310-6"},{"key":"2026041100282708000_2025.03.11.642683v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52885-3"},{"key":"2026041100282708000_2025.03.11.642683v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2012.03.009"},{"key":"2026041100282708000_2025.03.11.642683v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2018.06.008"},{"key":"2026041100282708000_2025.03.11.642683v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00023-5"},{"key":"2026041100282708000_2025.03.11.642683v1.13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66903"},{"key":"2026041100282708000_2025.03.11.642683v1.14","doi-asserted-by":"crossref","unstructured":"K. W. Timothy , R. Bauer , K. A. Larkin , E. P. Walsh , D. J. Abrams , C. Gonzalez Corcia , A. Valsamakis , G. S. Pitt , I. E. Dick , A. Golden , A Natural History Study of Timothy Syndrome. Orphanet J Rare Dis 19, 433 (2024).","DOI":"10.1186\/s13023-024-03445-x"},{"key":"2026041100282708000_2025.03.11.642683v1.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5482-12.2013"},{"key":"2026041100282708000_2025.03.11.642683v1.16","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-15-0322"},{"key":"2026041100282708000_2025.03.11.642683v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2023.11.001"},{"key":"2026041100282708000_2025.03.11.642683v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24114"},{"key":"2026041100282708000_2025.03.11.642683v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502506102"},{"key":"2026041100282708000_2025.03.11.642683v1.20","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.08638"},{"key":"2026041100282708000_2025.03.11.642683v1.21","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1898-07.2007"},{"key":"2026041100282708000_2025.03.11.642683v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2014.03.005"},{"key":"2026041100282708000_2025.03.11.642683v1.23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054166"},{"key":"2026041100282708000_2025.03.11.642683v1.24","doi-asserted-by":"crossref","unstructured":"G. D. Marquart , K. M. Tabor , M. Brown , J. L. Strykowski , G. K. Varshney , M. C. LaFave , T. Mueller , S. M. Burgess , S.-I. Higashijima , H. A. Burgess , A 3D Searchable Database of Transgenic Zebrafish Gal4 and Cre Lines for Functional Neuroanatomy Studies. Front Neural Circuits 9, 78 (2015).","DOI":"10.3389\/fncir.2015.00078"},{"key":"2026041100282708000_2025.03.11.642683v1.25","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giw015"},{"key":"2026041100282708000_2025.03.11.642683v1.26","doi-asserted-by":"crossref","unstructured":"V. Diep , L. H. Seaver , Long QT syndrome with craniofacial, digital, and neurologic features: Is it useful to distinguish between Timothy syndrome types 1 and 2? Am J Med Genet A 167A, 2780\u20132785 (2015).","DOI":"10.1002\/ajmg.a.37258"},{"key":"2026041100282708000_2025.03.11.642683v1.27","doi-asserted-by":"crossref","unstructured":"A.-M. Haapanen-Saaristo , N. Virtanen , E. Tcarenkova , K. Vaparanta , M. Ampuja , E.-R. Vehni\u00e4inen , I. Paatero , Heat stress sensitizes zebrafish embryos to neurological and cardiac toxicity. Biochemical and Biophysical Research Communications 733, 150682 (2024).","DOI":"10.1016\/j.bbrc.2024.150682"},{"key":"2026041100282708000_2025.03.11.642683v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/gene.1053"},{"key":"2026041100282708000_2025.03.11.642683v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.09.002"},{"key":"2026041100282708000_2025.03.11.642683v1.30","doi-asserted-by":"crossref","unstructured":"A. Arjun McKinney , R. Petrova , G. Panagiotakos , Calcium and activity-dependent signaling in the developing cerebral cortex. Development 149, dev198853 (2022).","DOI":"10.1242\/dev.198853"},{"key":"2026041100282708000_2025.03.11.642683v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2576"},{"key":"2026041100282708000_2025.03.11.642683v1.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028441"},{"key":"2026041100282708000_2025.03.11.642683v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/nature05300"},{"key":"2026041100282708000_2025.03.11.642683v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.01.034"},{"key":"2026041100282708000_2025.03.11.642683v1.35","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2357-17.2018"},{"key":"2026041100282708000_2025.03.11.642683v1.36","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5333-08.2009"},{"key":"2026041100282708000_2025.03.11.642683v1.37","doi-asserted-by":"crossref","unstructured":"W. Tang , J. D. Davidson , G. Zhang , K. E. Conen , J. Fang , F. Serluca , J. Li , X. Xiong , M. Coble , T. Tsai , G. Molind , C. H. Fawcett , E. Sanchez , P. Zhu , I. D. Couzin , M. C. Fishman , Genetic Control of Collective Behavior in Zebrafish. iScience 23, 100942 (2020).","DOI":"10.1016\/j.isci.2020.100942"},{"key":"2026041100282708000_2025.03.11.642683v1.38","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.179226"},{"key":"2026041100282708000_2025.03.11.642683v1.39","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1312-2"},{"key":"2026041100282708000_2025.03.11.642683v1.40","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.247446"},{"key":"2026041100282708000_2025.03.11.642683v1.41","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5500-11.2012"},{"key":"2026041100282708000_2025.03.11.642683v1.42","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.72825"},{"key":"2026041100282708000_2025.03.11.642683v1.43","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023949509487"},{"key":"2026041100282708000_2025.03.11.642683v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/BIOINFORMATICS\/BTZ931"},{"key":"2026041100282708000_2025.03.11.642683v1.45","doi-asserted-by":"crossref","unstructured":"Y. M. Bradford , C. E. Van Slyke , L. Ruzicka , A. Singer , A. Eagle , D. Fashena , D. G. Howe , K. Frazer , R. Martin , H. Paddock , C. Pich , S. Ramachandran , M. Westerfield , Zebrafish information network, the knowledgebase for Danio rerio research. Genetics 220, iyac016 (2022).","DOI":"10.1093\/genetics\/iyac016"},{"key":"2026041100282708000_2025.03.11.642683v1.46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7270.2007.00283.x"},{"key":"2026041100282708000_2025.03.11.642683v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"2026041100282708000_2025.03.11.642683v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0686-2"},{"key":"2026041100282708000_2025.03.11.642683v1.49","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.9.1953"},{"key":"2026041100282708000_2025.03.11.642683v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2007.06.004"},{"key":"2026041100282708000_2025.03.11.642683v1.51","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3401-1_9"},{"key":"2026041100282708000_2025.03.11.642683v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3041"},{"key":"2026041100282708000_2025.03.11.642683v1.53","doi-asserted-by":"publisher","DOI":"10.1002\/jez.b.23100"},{"key":"2026041100282708000_2025.03.11.642683v1.54","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1019-12.2012"},{"key":"2026041100282708000_2025.03.11.642683v1.55","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0615-07.2007"},{"key":"2026041100282708000_2025.03.11.642683v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0470-3"},{"key":"2026041100282708000_2025.03.11.642683v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.04.034"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.11.642683","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T07:28:36Z","timestamp":1775892516000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.03.11.642683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,14]]},"references-count":57,"URL":"https:\/\/doi.org\/10.1101\/2025.03.11.642683","relation":{},"subject":[],"published":{"date-parts":[[2025,3,14]]},"subtype":"preprint"}}