{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:59:59Z","timestamp":1773709199670,"version":"3.50.1"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004012","name":"Jane ja Aatos Erkon S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015736","name":"Folkh\u00e4lsanin Tutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010135","name":"Finska L\u00e4kares\u00e4llskapet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010135","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010116","name":"Medicinska Underst\u00f6dsf\u00f6reningen Liv och H\u00e4lsa","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010116","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007797","name":"University of Helsinki","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Variants in\n                      <jats:italic>CASQ1<\/jats:italic>\n                      , encoding a calcium-binding protein in the fast-twitch fibers of skeletal muscle, cause sarcoplasmic reticulum aberrations such as large vacuoles with CASQ1 inclusions or, less commonly, tubular aggregates. To date, seven pathogenic variants have been described, all dominant missense variants. The typical symptoms of the disease include muscle weakness, cramps, myalgia, and fatigue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used genome and exome sequencing to identify the disease-causing variants in two families with dominant myopathy. The candidate variants were further characterized by cell-transfection studies and western blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In Family 1, three patients presented with exercise intolerance, cramps, and myalgia. Additionally, the proband had muscle weakness and her muscle biopsy showed nemaline bodies. In electron microscopy, there were morphological changes in the triads and the SR-feet in all patients. A variant in\n                      <jats:italic>CASQ1<\/jats:italic>\n                      , p.(Glu89Lys), was found in all patients, whereas the proband had also two compound heterozygous variants in\n                      <jats:italic>NEB<\/jats:italic>\n                      . In Family 2, three patients presented with progressive muscle weakness. The proband\u2019s muscle biopsy showed marked atrophy. The frameshift variant p.(Gly383Alafs*39) in\n                      <jats:italic>CASQ1<\/jats:italic>\n                      was found in all three patients. In silico analysis indicated that the variant results in protein extension, which was confirmed by western blotting of patient muscle. Cell-transfection studies showed that the variant protein forms aggregates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study expands the spectrum of pathogenic\n                      <jats:italic>CASQ1<\/jats:italic>\n                      variants. The morphological changes in the SR-feet indicate a novel pathogenetic mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-025-13512-3","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T07:57:44Z","timestamp":1764316664000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of novel CASQ1 variants in two families with unusual phenotypic features"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-4779","authenticated-orcid":false,"given":"Milla","family":"Laarne","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7568-4684","authenticated-orcid":false,"given":"Manu","family":"Jokela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3057-8738","authenticated-orcid":false,"given":"Fang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanna","family":"Huovinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0111-7281","authenticated-orcid":false,"given":"Cornelia","family":"Kornblum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3349-6877","authenticated-orcid":false,"given":"Jens","family":"Reimann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3549-558X","authenticated-orcid":false,"given":"Mridul","family":"Johari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9249-8480","authenticated-orcid":false,"given":"Anna","family":"Vihola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-5255","authenticated-orcid":false,"given":"Jaakko","family":"Sarparanta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bjarne","family":"Udd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7890-5713","authenticated-orcid":false,"given":"Peter","family":"Hackman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8276-0972","authenticated-orcid":false,"given":"Vilma-Lotta","family":"Lehtokari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7040-7266","authenticated-orcid":false,"given":"Katarina","family":"Pelin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"13512_CR1","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.spen.2006.06.005","volume":"13","author":"HH Goebel","year":"2006","unstructured":"Goebel HH, Muller HD (2006) Protein aggregate myopathies. Semin Pediatr Neurol 13:96\u2013103. https:\/\/doi.org\/10.1016\/j.spen.2006.06.005","journal-title":"Semin Pediatr Neurol"},{"key":"13512_CR2","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1093\/brain\/awl128","volume":"129","author":"G Tomelleri","year":"2006","unstructured":"Tomelleri G, Palmucci L, Tonin P, Mongini T, Marini M, L\u2019Erario R et al (2006) SERCA1 and calsequestrin storage myopathy: a new surplus protein myopathy. Brain 129:2085\u20132092. https:\/\/doi.org\/10.1093\/brain\/awl128","journal-title":"Brain"},{"key":"13512_CR3","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1002\/humu.22631","volume":"35","author":"D Rossi","year":"2014","unstructured":"Rossi D, Vezzani B, Galli L, Paolini C, Toniolo L, Pierantozzi E et al (2014) A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates. Hum Mutat 35:1163\u20131170. https:\/\/doi.org\/10.1002\/humu.22631","journal-title":"Hum Mutat"},{"key":"13512_CR4","doi-asserted-by":"publisher","first-page":"e0155516","DOI":"10.1371\/journal.pone.0155516","volume":"11","author":"MC D\u2019Adamo","year":"2016","unstructured":"D\u2019Adamo MC, Sforna L, Visentin S, Grottesi A, Servettini L, Guglielmi L et al (2016) A calsequestrin-1 mutation associated with a skeletal muscle disease alters sarcoplasmic Ca2+ release. PLoS ONE 11:e0155516. https:\/\/doi.org\/10.1371\/journal.pone.0155516","journal-title":"PLoS ONE"},{"key":"13512_CR5","doi-asserted-by":"publisher","first-page":"28665","DOI":"10.1074\/jbc.M115.686261","volume":"290","author":"KM Lewis","year":"2015","unstructured":"Lewis KM, Ronish LA, Rios E, Kang C (2015) Characterization of two human skeletal calsequestrin mutants implicated in malignant hyperthermia and vacuolar aggregate myopathy. J Biol Chem 290:28665\u201328674. https:\/\/doi.org\/10.1074\/jbc.M115.686261","journal-title":"J Biol Chem"},{"key":"13512_CR6","doi-asserted-by":"publisher","first-page":"e1629","DOI":"10.1212\/WNL.0000000000006387","volume":"91","author":"C Semplicini","year":"2018","unstructured":"Semplicini C, Bertolin C, Bello L, Pantic B, Guidolin F, Vianello S et al (2018) The clinical spectrum of CASQ1-related myopathy. Neurology 91:e1629\u2013e1641. https:\/\/doi.org\/10.1212\/WNL.0000000000006387","journal-title":"Neurology"},{"key":"13512_CR7","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1136\/jmedgenet-2014-102882","volume":"52","author":"C Di Blasi","year":"2015","unstructured":"Di Blasi C, Sansanelli S, Ruggieri A, Moriggi M, Vasso M, D\u2019Adamo AP et al (2015) A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia. J Med Genet 52:617\u2013626. https:\/\/doi.org\/10.1136\/jmedgenet-2014-102882","journal-title":"J Med Genet"},{"issue":"12","key":"13512_CR8","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1002\/humu.23338","volume":"38","author":"V Barone","year":"2017","unstructured":"Barone V, Del Re V, Gamberucci A, Polverino V, Galli L, Rossi D, Costanzi E, Toniolo L, Berti G, Malandrini A, Ricci G, Siciliano G, Vattemi G, Tomelleri G, Pierantozzi E, Spinozzi S, Volpi N, Fulceri R, Battistutta R, Reggiani C, Sorrentino V (2017) Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy. Hum Mutat 38(12):1761\u20131773. https:\/\/doi.org\/10.1002\/humu.23338","journal-title":"Hum Mutat"},{"key":"13512_CR9","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s00401-017-1775-x","volume":"135","author":"J Bohm","year":"2018","unstructured":"Bohm J, Lornage X, Chevessier F, Birck C, Zanotti S, Cudia P et al (2018) CASQ1 mutations impair calsequestrin polymerization and cause tubular aggregate myopathy. Acta Neuropathol 135:149\u2013151. https:\/\/doi.org\/10.1007\/s00401-017-1775-x","journal-title":"Acta Neuropathol"},{"issue":"12","key":"13512_CR10","doi-asserted-by":"publisher","first-page":"e6689","DOI":"10.1002\/ccr3.6689","volume":"10","author":"KY Zhang","year":"2022","unstructured":"Zhang KY, Zhang GJ, Duan HQ, Li QX, Huang K, Xu LQ, Yang H, Luo YB (2022) CASQ1-related myopathy: the first report from China and the literature review. Clin Case Rep 10(12):e6689. https:\/\/doi.org\/10.1002\/ccr3.6689","journal-title":"Clin Case Rep"},{"key":"13512_CR11","doi-asserted-by":"publisher","first-page":"745","DOI":"10.3760\/cma.j.cn511374-20211229-01023","volume":"41","author":"X Guo","year":"2024","unstructured":"Guo X, Zhao Z, Shen H, Bing Q, Xie S, Hu J (2024) Identification of a novel variant in a patient with calsequestrin 1 related myopathy. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 41:745\u2013748. https:\/\/doi.org\/10.3760\/cma.j.cn511374-20211229-01023","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"13512_CR12","doi-asserted-by":"publisher","first-page":"4807","DOI":"10.1016\/S0021-9258(18)68857-X","volume":"263","author":"A Zarain-Herzberg","year":"1988","unstructured":"Zarain-Herzberg A, Fliegel L, MacLennan DH (1988) Structure of the rabbit fast-twitch skeletal muscle calsequestrin gene. J Biol Chem 263:4807\u20134812","journal-title":"J Biol Chem"},{"key":"13512_CR13","doi-asserted-by":"publisher","first-page":"8958","DOI":"10.1016\/S0021-9258(18)68401-7","volume":"263","author":"BT Scott","year":"1988","unstructured":"Scott BT, Simmerman HK, Collins JH, Nadal-Ginard B, Jones LR (1988) Complete amino acid sequence of canine cardiac calsequestrin deduced by cDNA cloning. J Biol Chem 263:8958\u20138964","journal-title":"J Biol Chem"},{"issue":"2","key":"13512_CR14","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/0014-5793(92)80241-8","volume":"299","author":"D Biral","year":"1992","unstructured":"Biral D, Volpe P, Damiani E, Margreth A (1992) Coexistence of two calsequestrin isoforms in rabbit slow-twitch skeletal muscle fibers. FEBS Lett 299(2):175\u2013178. https:\/\/doi.org\/10.1016\/0014-5793(92)80241-8","journal-title":"FEBS Lett"},{"key":"13512_CR15","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1042\/bj3010465","volume":"301","author":"P Volpe","year":"1994","unstructured":"Volpe P, Martini A, Furlan S, Meldolesi J (1994) Calsequestrin is a component of smooth muscles\u2014the skeletal-muscle and cardiac-muscle isoforms are both present, although in highly variable amounts and ratios. Biochem J 301:465\u2013469. https:\/\/doi.org\/10.1042\/bj3010465","journal-title":"Biochem J"},{"issue":"2","key":"13512_CR16","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1113\/jphysiol.2012.243444","volume":"591","author":"C Manno","year":"2013","unstructured":"Manno C, Sztretye M, Figueroa L, Allen PD, R\u00edos E (2013) Dynamic measurement of the calcium buffering properties of the sarcoplasmic reticulum in mouse skeletal muscle. J Physiol 591(2):423\u2013442. https:\/\/doi.org\/10.1113\/jphysiol.2012.243444","journal-title":"J Physiol"},{"key":"13512_CR17","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/S0006-3495(02)75396-4","volume":"82","author":"NA Beard","year":"2002","unstructured":"Beard NA, Sakowska MM, Dulhunty AF, Laver DR (2002) Calsequestrin is an inhibitor of skeletal muscle ryanodine receptor calcium release channels. Biophys J 82:310\u2013320. https:\/\/doi.org\/10.1016\/S0006-3495(02)75396-4","journal-title":"Biophys J"},{"key":"13512_CR18","doi-asserted-by":"publisher","first-page":"3444","DOI":"10.1529\/biophysj.104.051441","volume":"88","author":"NA Beard","year":"2005","unstructured":"Beard NA, Casarotto MG, Wei L, Vars\u00e1nyi M, Laver DR, Dulhunty AF (2005) Regulation of ryanodine receptors by calsequestrin: effect of high luminal Ca2+ and phosphorylation. Biophys J 88:3444\u20133454. https:\/\/doi.org\/10.1529\/biophysj.104.051441","journal-title":"Biophys J"},{"key":"13512_CR19","doi-asserted-by":"publisher","first-page":"11349","DOI":"10.1038\/srep11349","volume":"5","author":"L Wang","year":"2015","unstructured":"Wang L, Zhang L, Li S, Zheng Y, Yan X, Chen M et al (2015) Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin. Sci Rep 5:11349. https:\/\/doi.org\/10.1038\/srep11349","journal-title":"Sci Rep"},{"key":"13512_CR20","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1159\/000445574","volume":"38","author":"L Zhang","year":"2016","unstructured":"Zhang L, Wang L, Li S, Xue J, Luo D (2016) Calsequestrin-1 regulates store-operated Ca2+ entry by inhibiting STIM1 aggregation. Cell Physiol Biochem 38:2183\u20132193. https:\/\/doi.org\/10.1159\/000445574","journal-title":"Cell Physiol Biochem"},{"key":"13512_CR21","doi-asserted-by":"publisher","first-page":"16176","DOI":"10.1074\/jbc.M300120200","volume":"278","author":"H Park","year":"2003","unstructured":"Park H, Wu S, Dunker AK, Kang C (2003) Polymerization of calsequestrin. Implications for Ca2+ regulation. J Biol Chem 278:16176\u201316182. https:\/\/doi.org\/10.1074\/jbc.M300120200","journal-title":"J Biol Chem"},{"key":"13512_CR22","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1039\/c3mb25588c","volume":"9","author":"A Kumar","year":"2013","unstructured":"Kumar A, Chakravarty H, Bal NC, Balaraju T, Jena N, Misra G et al (2013) Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization. Mol Biosyst 9:1949\u20131957. https:\/\/doi.org\/10.1039\/c3mb25588c","journal-title":"Mol Biosyst"},{"key":"13512_CR23","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1074\/jbc.M311553200","volume":"279","author":"H Park","year":"2004","unstructured":"Park H, Park IY, Kim E, Youn B, Fields K, Dunker AK et al (2004) Comparing skeletal and cardiac calsequestrin structures and their calcium binding: a proposed mechanism for coupled calcium binding and protein polymerization. J Biol Chem 279:18026\u201318033. https:\/\/doi.org\/10.1074\/jbc.M311553200","journal-title":"J Biol Chem"},{"key":"13512_CR24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/bip.22534","volume":"103","author":"NC Bal","year":"2015","unstructured":"Bal NC, Jena N, Chakravarty H, Kumar A, Chi M, Balaraju T et al (2015) The C-terminal calcium-sensitive disordered motifs regulate isoform-specific polymerization characteristics of calsequestrin. Biopolymers 103:15\u201322. https:\/\/doi.org\/10.1002\/bip.22534","journal-title":"Biopolymers"},{"key":"13512_CR25","doi-asserted-by":"publisher","first-page":"E638","DOI":"10.1073\/pnas.1620265114","volume":"114","author":"C Manno","year":"2017","unstructured":"Manno C, Figueroa LC, Gillespie D, Fitts R, Kang C, Franzini-Armstrong C et al (2017) Calsequestrin depolymerizes when calcium is depleted in the sarcoplasmic reticulum of working muscle. Proc Natl Acad Sci U S A 114:E638\u2013E647. https:\/\/doi.org\/10.1073\/pnas.1620265114","journal-title":"Proc Natl Acad Sci U S A"},{"key":"13512_CR26","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/j.nmd.2021.07.012","volume":"31","author":"J Laitila","year":"2021","unstructured":"Laitila J, Wallgren-Pettersson C (2021) Recent advances in nemaline myopathy. Neuromuscul Disord 31:955\u2013967. https:\/\/doi.org\/10.1016\/j.nmd.2021.07.012","journal-title":"Neuromuscul Disord"},{"issue":"4","key":"13512_CR27","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1093\/brain\/86.4.793","volume":"86","author":"GM Shy","year":"1963","unstructured":"Shy GM, Engel WK, Somers JE, Wanko T (1963) Nemaline myopathy. A new congenital myopathy. Brain 86(4):793\u2013810. https:\/\/doi.org\/10.1093\/brain\/86.4.793","journal-title":"Brain"},{"key":"13512_CR28","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1002\/humu.22693","volume":"35","author":"VL Lehtokari","year":"2014","unstructured":"Lehtokari VL, Kiiski K, Sandaradura SA, Laporte J, Repo P, Frey JA et al (2014) Mutation update: the spectra of nebulin variants and associated myopathies. Hum Mutat 35:1418\u20131426. https:\/\/doi.org\/10.1002\/humu.22693","journal-title":"Hum Mutat"},{"key":"13512_CR29","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1073\/pnas.96.5.2305","volume":"96","author":"K Pelin","year":"1999","unstructured":"Pelin K, Hilpela P, Donner K, Sewry C, Akkari PA, Wilton SD et al (1999) Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A 96:2305\u20132310. https:\/\/doi.org\/10.1073\/pnas.96.5.2305","journal-title":"Proc Natl Acad Sci U S A"},{"key":"13512_CR30","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1056\/NEJMoa1516767","volume":"376","author":"JE Posey","year":"2017","unstructured":"Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH et al (2017) Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med 376:21\u201331. https:\/\/doi.org\/10.1056\/NEJMoa1516767","journal-title":"N Engl J Med"},{"key":"13512_CR31","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.nmd.2015.10.003","volume":"26","author":"A Evil\u00e4","year":"2016","unstructured":"Evil\u00e4 A, Arumilli M, Udd B, Hackman P (2016) Targeted next-generation sequencing assay for detection of mutations in primary myopathies. Neuromuscul Disord 26:7\u201315. https:\/\/doi.org\/10.1016\/j.nmd.2015.10.003","journal-title":"Neuromuscul Disord"},{"key":"13512_CR32","doi-asserted-by":"publisher","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","volume":"51","author":"C UniProt","year":"2023","unstructured":"UniProt C (2023) UniProt: the universal protein knowledgebase in 2023. Nucleic Acids Res 51:D523\u2013D531. https:\/\/doi.org\/10.1093\/nar\/gkac1052","journal-title":"Nucleic Acids Res"},{"key":"13512_CR33","doi-asserted-by":"publisher","first-page":"D513","DOI":"10.1093\/nar\/gkad1020","volume":"52","author":"AM Altenhoff","year":"2024","unstructured":"Altenhoff AM, Warwick Vesztrocy A, Bernard C, Train CM, Nicheperovich A, Prieto Banos S et al (2024) OMA orthology in 2024: improved prokaryote coverage, ancestral and extant GO enrichment, a revamped synteny viewer and more in the OMA Ecosystem. Nucleic Acids Res 52:D513\u2013D521. https:\/\/doi.org\/10.1093\/nar\/gkad1020","journal-title":"Nucleic Acids Res"},{"key":"13512_CR34","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1093\/bioinformatics\/btp033","volume":"25","author":"AM Waterhouse","year":"2009","unstructured":"Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ (2009) Jalview version 2\u2013a multiple sequence alignment editor and analysis workbench. Bioinformatics 25:1189\u20131191. https:\/\/doi.org\/10.1093\/bioinformatics\/btp033","journal-title":"Bioinformatics"},{"key":"13512_CR35","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","volume":"99","author":"NM Ioannidis","year":"2016","unstructured":"Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S et al (2016) Revel: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99:877\u2013885. https:\/\/doi.org\/10.1016\/j.ajhg.2016.08.016","journal-title":"Am J Hum Genet"},{"key":"13512_CR36","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47:D886\u2013D894. https:\/\/doi.org\/10.1093\/nar\/gky1016","journal-title":"Nucleic Acids Res"},{"key":"13512_CR37","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s13073-022-01120-z","volume":"14","author":"C Li","year":"2022","unstructured":"Li C, Zhi D, Wang K, Liu X (2022) MetaRNN: differentiating rare pathogenic and rare benign missense SNVs and InDels using deep learning. Genome Med 14:115. https:\/\/doi.org\/10.1186\/s13073-022-01120-z","journal-title":"Genome Med"},{"key":"13512_CR38","doi-asserted-by":"publisher","first-page":"eadg7492","DOI":"10.1126\/science.adg7492","volume":"381","author":"J Cheng","year":"2023","unstructured":"Cheng J, Novati G, Pan J, Bycroft C, \u017demgulyt\u0117 A, Applebaum T et al (2023) Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381:eadg7492. https:\/\/doi.org\/10.1126\/science.adg7492","journal-title":"Science"},{"issue":"W1","key":"13512_CR39","doi-asserted-by":"publisher","first-page":"W446","DOI":"10.1093\/nar\/gkab266","volume":"49","author":"R Steinhaus","year":"2021","unstructured":"Steinhaus R, Proft S, Schuelke M, Cooper DN, Schwarz JM, Seelow D (2021) MutationTaster2021. Nucleic Acids Res 49(W1):W446\u2013W451. https:\/\/doi.org\/10.1093\/nar\/gkab266","journal-title":"Nucleic Acids Res"},{"key":"13512_CR40","doi-asserted-by":"publisher","first-page":"2811","DOI":"10.1093\/bioinformatics\/btab051","volume":"37","author":"M Lefter","year":"2021","unstructured":"Lefter M, Vis JK, Vermaat M, den Dunnen JT, Taschner PEM, Laros JFJ (2021) Mutalyzer 2: next generation HGVS nomenclature checker. Bioinformatics 37:2811\u20132817. https:\/\/doi.org\/10.1093\/bioinformatics\/btab051","journal-title":"Bioinformatics"},{"key":"13512_CR41","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30","journal-title":"Genet Med"},{"key":"13512_CR42","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1002\/humu.23626","volume":"39","author":"AN Abou Tayoun","year":"2018","unstructured":"Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG et al (2018) Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion. Hum Mutat 39:1517\u20131524. https:\/\/doi.org\/10.1002\/humu.23626","journal-title":"Hum Mutat"},{"key":"13512_CR43","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13395-015-0029-7","volume":"5","author":"NA Beard","year":"2015","unstructured":"Beard NA, Dulhunty AF (2015) C-terminal residues of skeletal muscle calsequestrin are essential for calcium binding and for skeletal ryanodine receptor inhibition. Skelet Muscle 5:6. https:\/\/doi.org\/10.1186\/s13395-015-0029-7","journal-title":"Skelet Muscle"},{"key":"13512_CR44","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/s0005-2736(01)00406-0","volume":"1515","author":"L Glover","year":"2001","unstructured":"Glover L, Culligan K, Cala S, Mulvey C, Ohlendieck K (2001) Calsequestrin binds to monomeric and complexed forms of key calcium-handling proteins in native sarcoplasmic reticulum membranes from rabbit skeletal muscle. Biochim Biophys Acta 1515:120\u2013132. https:\/\/doi.org\/10.1016\/s0005-2736(01)00406-0","journal-title":"Biochim Biophys Acta"},{"key":"13512_CR45","doi-asserted-by":"publisher","first-page":"23389","DOI":"10.1074\/jbc.272.37.23389","volume":"272","author":"L Zhang","year":"1997","unstructured":"Zhang L, Kelley J, Schmeisser G, Kobayashi YM, Jones LR (1997) Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane. J Biol Chem 272:23389\u201323397. https:\/\/doi.org\/10.1074\/jbc.272.37.23389","journal-title":"J Biol Chem"},{"key":"13512_CR46","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/s0014-5793(00)02246-8","volume":"486","author":"DW Shin","year":"2000","unstructured":"Shin DW, Ma J, Kim DH (2000) The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca(2+) and interacts with triadin. FEBS Lett 486:178\u2013182. https:\/\/doi.org\/10.1016\/s0014-5793(00)02246-8","journal-title":"FEBS Lett"},{"key":"13512_CR47","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1038\/nsb0698-476","volume":"5","author":"S Wang","year":"1998","unstructured":"Wang S, Trumble WR, Liao H, Wesson CR, Dunker AK, Kang C (1998) Crystal structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulum. Nat Struct Biol 5:476\u2013483. https:\/\/doi.org\/10.1038\/nsb0698-476","journal-title":"Nat Struct Biol"},{"key":"13512_CR48","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/331315a0","volume":"331","author":"F Anthony Lai","year":"1988","unstructured":"Anthony Lai F, Erickson HP, Rousseau E, Liu Q-Y, Meissner G (1988) Purification and reconstitution of the calcium release channel from skeletal muscle. Nature 331:315\u2013319. https:\/\/doi.org\/10.1038\/331315a0","journal-title":"Nature"},{"key":"13512_CR49","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1007\/s10974-011-9277-2","volume":"32","author":"F Protasi","year":"2011","unstructured":"Protasi F, Paolini C, Canato M, Reggiani C, Quarta M (2011) Lessons from calsequestrin-1 ablation in vivo: much more than a Ca2+ buffer after all. J Muscle Res Cell M 32:257\u2013270. https:\/\/doi.org\/10.1007\/s10974-011-9277-2","journal-title":"J Muscle Res Cell M"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-025-13512-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-025-13512-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-025-13512-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T15:29:15Z","timestamp":1765812555000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-025-13512-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":49,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["13512"],"URL":"https:\/\/doi.org\/10.1007\/s00415-025-13512-3","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"assertion":[{"value":"1 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflicts of interest that are relevant to the content of this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"Written informed consent was obtained from all participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The study has been approved by the Ethics Committee of the Children\u2019s Hospital, and the Helsinki University Hospital, University of Helsinki, Helsinki, Finland (HUS\/1001\/2021), and was performed in accordance with the Declaration of Helsinki.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical standards"}}],"article-number":"789"}}