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Pathogenic variants in different EC coupling components have previously been associated with various neuromuscular disorders. In this study we aimed to identify the genetic etiology of a muscular condition characterized by early-onset muscle weakness, elevated CK, ptosis and low body weight, which was observed in three individuals from two unrelated consanguineous families. Exome sequencing (ES) performed in multiple individuals of one family, and ES in combination with SNP array-based homozygosity mapping in the proband of the other family, revealed different homozygous loss-of-function variants in the second exon of\n                    <jats:italic>CACNB1<\/jats:italic>\n                    in the affected individuals from each family.\n                    <jats:italic>CACNB1<\/jats:italic>\n                    encodes the \u03b21 subunit of the skeletal muscle dihydropyridine receptor (DHPR), a voltage-gated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel with a major role in EC coupling. Molecular impact of the identified variants was assessed in LHCN-M2 human myoblasts. Long-read RNA sequencing in LHCN-M2 wild-type myotubes showed that in differentiated skeletal muscle cells virtually all\n                    <jats:italic>CACNB1<\/jats:italic>\n                    transcript isoforms contain exon 2 and will therefore be affected by genetic variants in this exon. Pathogenicity of the identified\n                    <jats:italic>CACNB1<\/jats:italic>\n                    variants was further validated by replicating one of them (c.85-1G&gt;A) in LHCN-M2 cells using CRISPR-Cas9-mediated base-editing. Analysis of LHCN-M2 edited myotubes demonstrated that in addition to the loss of \u03b21 subunits, these cells displayed severely reduced protein levels of \u03b11S, the pore-forming subunit of DHPR. We conclude that pathogenic variants in\n                    <jats:italic>CACNB1<\/jats:italic>\n                    cause a new congenital muscular disorder.\n                  <\/jats:p>","DOI":"10.1038\/s41431-025-01944-4","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T16:46:02Z","timestamp":1759164362000},"page":"314-323","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["N-terminal truncating variants in CACNB1 cause a new congenital muscular disorder"],"prefix":"10.1038","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7896-8519","authenticated-orcid":false,"given":"Asier","family":"Iturrate","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8018-226X","authenticated-orcid":false,"given":"Nurit","family":"Assia Batzir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranit","family":"Jaron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Garcia-Valentin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Nevado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jair","family":"Tenorio-Castano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-4825","authenticated-orcid":false,"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamila","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1315-6835","authenticated-orcid":false,"given":"Rotem","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dvora","family":"Sassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"Aharoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alla","family":"Kuzminsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6327-5138","authenticated-orcid":false,"given":"Lina","family":"Basel-Salmon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naama","family":"Orenstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yakov","family":"Fellig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shay","family":"Ben-Shachar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3386-9824","authenticated-orcid":false,"given":"Dina","family":"Marek-Yagel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0635-3619","authenticated-orcid":false,"given":"Victor L.","family":"Ruiz-Perez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"1944_CR1","doi-asserted-by":"publisher","first-page":"a003947","DOI":"10.1101\/cshperspect.a003947","volume":"3","author":"WA Catterall","year":"2011","unstructured":"Catterall WA. 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For family 2, research studies were approved by the Institutional Ethics Committees of Medical Research Institute-Alexandria University, Hospital La Paz (PI-6270) and CSIC. Written informed consent was obtained from all participants or their parents for genetic analysis and publication of clinical and molecular data.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}