title: The first knockin mouse model of episodic ataxia type 2.
abstract: Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Rose
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Kriener
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Heinzer
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Xueliang
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Raike
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands; Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: ellen.hess@emory.edu.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Hess
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics; D002531:Cerebellum / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D009474:Neurons / Q000502:physiology; D009759:Nystagmus, Pathologic / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011930:Reaction Time / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D047908:Intracellular Signaling Peptides and Proteins; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; C105159:SH3GL1 protein, human
keywords: Ataxia; CACNA1A; Cerebellar granule cell; Channelopathy; Cre; EA2; Episodic ataxia type 2; Knockin; Purkinje cell; Voltage-gated calcium channel
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