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dc.contributor.authorKramer, A. A.
dc.contributor.authorGrosso, B. J.
dc.contributor.authorTyagi, S.
dc.contributor.authorBennett, D. F.
dc.contributor.authorWangler, M. F.
dc.contributor.authorMeza, U.
dc.contributor.authorBannister, R. A.
dc.date.accessioned2022-02-21T19:53:56Z
dc.date.available2022-02-21T19:53:56Z
dc.date.issued2022-02
dc.identifier.urihttp://hdl.handle.net/10713/18067
dc.descriptionPoster presented at the Biophysical Society Annual Meeting Feb 19-23, 2022.en_US
dc.description.abstractCa2+ flux into nerve terminals via CaV2.1 channels is essential for active neurotransmitter release at neuromuscular junctions and many central synapses. Mutations in CACNA1A, the gene encoding the principal CaV2.1 α1A subunit, cause a broad spectrum of neurological disorders. Typically, gain-of-function (GOF) mutations are associated with migraine andepilepsy while loss-of-function (LOF) mutations are causative for episodic and congenital ataxias. However, a cluster of severe CaV2.1 channelopathies have overlapping presentations which suggests that channel dysfunction in these disorders cannot always be defined bimodally as GOF or LOF. In particular, the R1667P mutation causes focal seizures, generalized hypotonia, dysarthria, congenital ataxia and, in onecase, cerebral edema leading ultimately to death. Here, we demonstrate that the R1667P mutation causes both channel GOF (hyperpolarizing voltage-dependence of activation, slowed deactivation) and LOF (slowed activation kinetics) when expressed heterologously in tsA-201 cells. We also observed a substantial reduction in Ca2+ current density in this heterologous system. In summary, our findings indicate a complex functional effect of R1667P and support the idea that pathological missense mutations in CaV2.1 may not represent exclusively GOF or LOF.en_US
dc.language.isoen_USen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectCaV 2.1 channel gatingen_US
dc.subjectCACNA1A varianten_US
dc.subjectloss-of-function mutationen_US
dc.subject.meshNeurodevelopmental Disordersen_US
dc.subject.meshNeurotransmitter Agentsen_US
dc.subject.meshNeuromuscular Junctionen_US
dc.subject.meshSynapsesen_US
dc.subject.meshGain of Function Mutationen_US
dc.subject.meshChannelopathiesen_US
dc.subject.meshMutation, Missenseen_US
dc.titleComplex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorderen_US
dc.typePoster/Presentationen_US
refterms.dateFOA2022-02-21T19:53:56Z


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International