{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:49:08Z","timestamp":1753890548154,"version":"3.41.2"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:00Z","timestamp":1683072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000615","name":"Fight for Sight UK","doi-asserted-by":"publisher","award":["5079\/5080"],"award-info":[{"award-number":["5079\/5080"]}],"id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Pathogenic, generally loss-of-function, variants in <jats:italic>CACNA1F<\/jats:italic>, encoding the Ca<jats:sub>v<\/jats:sub>1.4\u03b1<jats:sub>1<\/jats:sub> calcium channel, underlie congenital stationary night blindness type 2 (CSNB2), a rare inherited retinal disorder associated with visual disability. To establish the underlying pathomechanism, we investigated 10 clinically derived <jats:italic>CACNA1F<\/jats:italic> missense variants located across pore-forming domains, connecting loops, and the carboxy-tail domain of the Ca<jats:sub>v<\/jats:sub>1.4\u03b1 subunit. Homology modeling showed that all variants cause steric clashes; informatics analysis correctly predicted pathogenicity for 7\/10 variants. <jats:italic>In vitro<\/jats:italic> analyses demonstrated that all variants cause a decrease in current, global expression, and protein stability and act through a loss-of-function mechanism and suggested that the mutant Ca<jats:sub>v<\/jats:sub>1.4\u03b1 proteins were degraded by the proteasome. We showed that the reduced current for these variants could be significantly increased through treatment with clinical proteasome inhibitors. In addition to facilitating clinical interpretation, these studies suggest that proteasomal inhibition represents an avenue of potential therapeutic intervention for CSNB2.<\/jats:p>","DOI":"10.3389\/fcell.2023.1161548","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T04:40:25Z","timestamp":1683088825000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cav1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation"],"prefix":"10.3389","volume":"11","author":[{"given":"Tal T.","family":"Sadeh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard A.","family":"Baines","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme C.","family":"Black","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Forbes","family":"Manson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1161\/01.cir.102.8.921","article-title":"Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome","volume":"102","author":"Abriel","year":"2000","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1161\/CIRCULATIONAHA.106.668392","article-title":"Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death","volume":"115","author":"Antzelevitch","year":"2007","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1093\/hmg\/ddw387","article-title":"Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration","volume":"26","author":"Athanasiou","year":"2017","journal-title":"Hum. 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