title: The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated alpha 2 delta-2 protein with abnormal function.
abstract: The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and cerebellar ataxia. A mutation in Cacna2d2, the gene encoding the alpha 2 delta-2 voltage-dependent calcium channel accessory subunit, has been found to underlie the ducky phenotype. The alpha 2 delta-2 mRNA is strongly expressed in cerebellar Purkinje cells. We show that du/du mice have abnormalities in their Purkinje cell dendritic tree. The mutation in alpha 2 delta-2 results in the introduction of a premature stop codon and predicts the expression of a truncated protein encoded by the first three exons of Cacna2d2, followed by 8 novel amino acids. We show that both mRNA and protein corresponding to this predicted transcript are expressed in du/du cerebellum and present in Purkinje cells. Whereas the alpha 2 delta-2 subunit increased the peak current density of the Ca(V)2.1/beta(4) channel combination when co-expressed in vitro, co-expression with the truncated mutant alpha 2 delta-2 protein reduced current density, indicating that it may contribute to the du phenotype.
authors.affiliation: Department of Pharmacology, University College London, Gower Street, London WC1E, United Kingdom.
authors.forename: Jens
authors.initials: J
authors.lastname: Brodbeck
authors.forename: Anthony
authors.initials: A
authors.lastname: Davies
authors.forename: Jo-Maree
authors.initials: JM
authors.lastname: Courtney
authors.forename: Alon
authors.initials: A
authors.lastname: Meir
authors.forename: Nuria
authors.initials: N
authors.lastname: Balaguero
authors.forename: Carles
authors.initials: C
authors.lastname: Canti
authors.forename: Fraser J
authors.initials: FJ
authors.lastname: Moss
authors.forename: Karen M
authors.initials: KM
authors.lastname: Page
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Pratt
authors.forename: Steven P
authors.initials: SP
authors.lastname: Hunt
authors.forename: Jane
authors.initials: J
authors.lastname: Barclay
authors.forename: Michele
authors.initials: M
authors.lastname: Rees
authors.forename: Annette C
authors.initials: AC
authors.lastname: Dolphin
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019556:COS Cells; D015220:Calcium Channels / Q000737:chemistry* / Q000235:genetics*; D020746:Calcium Channels, L-Type; D002531:Cerebellum / Q000378:metabolism; D018388:Codon, Terminator; D018076:DNA, Complementary / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D004195:Disease Models, Animal; D004594:Electrophysiology; D005456:Fluorescent Dyes / Q000494:pharmacology; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011689:Purkinje Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014162:Transfection; D014981:Xenopus
chemical_list: D000596:Amino Acids; C486060:Cacna2d1 protein, rat; C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D018388:Codon, Terminator; D018076:DNA, Complementary; D005456:Fluorescent Dyes; D007546:Isoquinolines; D012333:RNA, Messenger; C070614:neurobiotin; D001710:Biotin; C017475:lucifer yellow