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Missense and nonsense mutations in\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    , the gene that encodes the principal \u03b1\n                    <jats:sub>1A<\/jats:sub>\n                    subunit of the Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.1 channel complex, are well\u2010known to cause Episodic Ataxia type 2 (EA2) and Familial Hemiplegic Migraine type 1 (FHM1). These Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.1 channelopathies are typically caused by either channel loss\/reduction\u2010of\u2010function (LOF) or gain\u2010of\u2010function (GOF), respectively. However, recent genome\u2010wide sequencing has revealed that point mutations in Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.1, in fact, underlie a spectrum of neurological disorders that feature epilepsy, tremor, nystagmus, hypotonia, cerebellar atrophy, cognitive deficits, and global developmental delay. Given the multiple manifestations of the mutations and the broad range of severity among these disorders, the assessment of the impact of an individual pathological mutation on channel function is essential for understanding the etiology of a given case. To this end, we expressed the rat orthologues of one newly identified and one previously reported, but yet to be characterized, human Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.1 variants (V176M and R1673C, respectively) in HEK 293 cells and investigated their biophysical properties using patch\u2010clamp electrophysiology. The corresponding rat variants (V178M and R1624C, respectively) had multiple effects on channel function, though each mutation affected channel gating differently. V178M displayed a ~10\u2009mV hyperpolarizing shift in activation and slowed deactivation, while R1624C slowed channel activation kinetics, delayed closure, and accelerated recovery from inactivation. Molecular modeling revealed structural alterations that may account for the observed changes in channel gating. Taken together, our results indicate that V176M and R1673C likely cause human Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.1 channelopathies through multiple, distinct mechanisms.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501708r","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T14:25:15Z","timestamp":1756995915000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Altered Gating of Two\n                    <scp>\n                      Ca\n                      <sub>V<\/sub>\n                      2.1\n                    <\/scp>\n                    Variants Linked to Neurodevelopmental Disorders With Epilepsy and Migraine"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8604-3906","authenticated-orcid":false,"given":"Ulises","family":"Meza","sequence":"first","affiliation":[{"name":"Department of 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