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Disruption of this tightly controlled process is associated with a wide spectrum of human diseases. Dysfunction can result from a multitude of remodeling mechanisms, including altered protein expression (up- or downregulation), assembly remodeling, or mutations. We focus in particular on Orai1 mutations, which have been linked to severe combined immunodeficiency (SCID) as a result of channel loss-of-function (LoF), as well as to disorders like tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) arising from gain-of-function (GoF) alterations. These mutation-induced functional defects can be attributed to a wide variety of disruptions in the complex activation cascade of the Orai1 channel. Under physiological conditions, Orai1 activation involves all four transmembrane (TM) domains and follows a sophisticated interaction mechanism that ensures accurate signal transmission from the protein periphery toward its central Ca2+-conducting pore. In this Review, we compile all currently known disease-associated Orai1 mutations, delineate the mechanisms by which they interfere with the activation cascade, and discuss their pathological relevance. Their widespread distribution across all the domains of this Ca2+ channel highlights that malfunctions at virtually any point along the Orai1 TM domain interfaces can profoundly impair its activation mechanism, ultimately leading to severe diseases.<\/jats:p>","DOI":"10.1085\/jgp.202614031","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:20:33Z","timestamp":1786515633000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["The many faces of Orai1 dysfunction: Molecular mechanisms and clinical manifestations"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9677-2088","authenticated-orcid":true,"given":"Magdalena","family":"Prantl","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052r2xn60","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz 1 , Linz,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9041-7455","authenticated-orcid":true,"given":"Lara","family":"Atzgerstorfer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052r2xn60","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz 1 , Linz,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2385-717X","authenticated-orcid":true,"given":"Tamara","family":"Radiskovic","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052r2xn60","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz 1 , Linz,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-0158","authenticated-orcid":true,"given":"Marc","family":"Fahrner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052r2xn60","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz 1 , Linz,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4768-146X","authenticated-orcid":true,"given":"Isabella","family":"Derler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052r2xn60","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz 1 , Linz,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"2026083109060390500_bib1","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.synbio.2025.02.005","article-title":"Modulating ion channels with nanobodies","volume":"10","author":"Ali","year":"2025","journal-title":"Synth. 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