{"doi":"10.1093/brain/awac081","title":"Biallelic <i>CACNA2D1</i> loss-of-function variants cause early-onset developmental epileptic encephalopathy","abstract":"Voltage-gated calcium (CaV) channels form three subfamilies (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1-4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-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 α2δ-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>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface and a complete inability of α2δ-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 α2δ-1 and other α2δ proteins for normal human neuronal development.","journal":"Brain","year":2022,"id":241456,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9426,"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":730164,"name":"Leonie von Elsner","orcid":"0000-0002-0578-9317","position":1,"is_corresponding":false},{"id":870366,"name":"Tess Holling","orcid":"0000-0001-9550-2270","position":2,"is_corresponding":false},{"id":870801,"name":"Lauren Mattas","orcid":null,"position":3,"is_corresponding":false},{"id":870802,"name":"Jess Pickard","orcid":null,"position":4,"is_corresponding":false},{"id":282680,"name":"Davor Lessel","orcid":"0000-0003-4496-244X","position":5,"is_corresponding":false},{"id":870367,"name":"Kjara S Pilch","orcid":"0000-0003-2145-2535","position":6,"is_corresponding":false},{"id":870368,"name":"Ivan Kadurin","orcid":"0000-0002-7720-367X","position":7,"is_corresponding":false},{"id":870803,"name":"Wendy S. Pratt","orcid":null,"position":8,"is_corresponding":false},{"id":317405,"name":"Igor B. Zhulin","orcid":"0000-0002-6708-5323","position":9,"is_corresponding":false},{"id":249403,"name":"Hongzheng Dai","orcid":"0000-0002-0103-876X","position":10,"is_corresponding":false},{"id":585668,"name":"Maja Hempel","orcid":"0000-0003-0609-2738","position":11,"is_corresponding":false},{"id":298496,"name":"Maura Ruzhnikov","orcid":"0000-0001-9610-1612","position":12,"is_corresponding":false},{"id":513907,"name":"Kerstin Kutsche","orcid":null,"position":13,"is_corresponding":false},{"id":858685,"name":"Annette Dolphin","orcid":"0000-0003-4626-4856","position":14,"is_corresponding":false},{"id":870800,"name":"Shehrazade Dahimène","orcid":null,"position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-19T00:22:56.227656Z","pmid":"35293990","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":[]}