{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:17:30Z","timestamp":1790749050012,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["206279\\Z\\17\\Z"],"award-info":[{"award-number":["206279\\Z\\17\\Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R35GM131760"],"award-info":[{"award-number":["1R35GM131760"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["1240\/6-2"],"award-info":[{"award-number":["1240\/6-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["1240\/10-1"],"award-info":[{"award-number":["1240\/10-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Voltage-gated calcium (CaV) channels form three subfamilies (CaV1\u20133). The CaV1 and CaV2 channels are heteromeric, consisting of an \u03b11 pore-forming subunit, associated with auxiliary CaV\u03b2 and \u03b12\u03b4 subunits. The \u03b12\u03b4 subunits are encoded in mammals by four genes, CACNA2D1\u20134. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the \u03b12\u03b4-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy. Patient 1 has a homozygous frameshift variant c.818_821dup\/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of \u03b12\u03b4-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup\/p.(Leu9Alafs*5), highly probably representing a null allele and a missense variant c.626G&amp;gt;A\/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of \u03b12\u03b4-1 as a calcium channel subunit, with strongly reduced trafficking of \u03b12\u03b4-1G209D to the cell surface and a complete inability of \u03b12\u03b4-1G209D to increase the trafficking and function of CaV2 channels. Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of \u03b12\u03b4-1 and other \u03b12\u03b4 proteins for normal human neuronal development.<\/jats:p>","DOI":"10.1093\/brain\/awac081","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T12:22:15Z","timestamp":1645791735000},"page":"2721-2729","source":"Crossref","is-referenced-by-count":43,"title":["Biallelic <i>CACNA2D1<\/i> loss-of-function variants cause early-onset developmental epileptic encephalopathy"],"prefix":"10.1093","volume":"145","author":[{"given":"Shehrazade","family":"Dahimene","sequence":"first","affiliation":[{"name":"Department of Neuroscience Physiology and Pharmacology, University College London (UCL) , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"von Elsner","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tess","family":"Holling","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren S","family":"Mattas","sequence":"additional","affiliation":[{"name":"Neurology and Neurological Sciences, Pediatrics, Division of Medical Genetics, Stanford University and Lucile Packard Children's Hospital , Palo Alto, CA 94304 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jess","family":"Pickard","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Physiology and Pharmacology, University College London (UCL) , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4496-244X","authenticated-orcid":false,"given":"Davor","family":"Lessel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjara S","family":"Pilch","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Physiology and Pharmacology, University College London (UCL) , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Kadurin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Physiology and Pharmacology, University College London (UCL) , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy S","family":"Pratt","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Physiology and Pharmacology, University College London (UCL) , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6708-5323","authenticated-orcid":false,"given":"Igor B","family":"Zhulin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Translational Data Analytics Institute, The Ohio State University , Columbus, OH, 43210 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzheng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine\/NGS-Molecular, Baylor Genetics , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Hempel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura R Z","family":"Ruzhnikov","sequence":"additional","affiliation":[{"name":"Neurology and Neurological Sciences, Pediatrics, Division of Medical Genetics, Stanford University and Lucile Packard Children's Hospital , Palo Alto, CA 94304 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-8963","authenticated-orcid":false,"given":"Kerstin","family":"Kutsche","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , 20246 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4626-4856","authenticated-orcid":false,"given":"Annette C","family":"Dolphin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Physiology and Pharmacology, University College London (UCL) , London WC1E 6BT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,16]]},"reference":[{"key":"2022082719583054000_awac081-B1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1146\/annurev-pharmtox-010818-021757","article-title":"Structure and pharmacology of voltage-gated sodium and calcium channels","volume":"60","author":"Catterall","year":"2020","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2022082719583054000_awac081-B2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41583-020-0278-2","article-title":"Presynaptic calcium channels: Specialized control of synaptic neurotransmitter release","volume":"21","author":"Dolphin","year":"2020","journal-title":"Nat Rev Neurosci"},{"key":"2022082719583054000_awac081-B3","doi-asserted-by":"crossref","first-page":"14738","DOI":"10.1016\/S0021-9258(18)77174-3","article-title":"Subunits of purified calcium channels. \u03b12 and \u03b4 are encoded by the same 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