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

• Published in: The Journal of biological chemistry Vol. 277; no. 10; pp. 7684 - 7693
• Main Authors: Brodbeck, Jens, Davies, Anthony, Courtney, Jo-Maree, Meir, Alon, Balaguero, Nuria, Canti, Carles, Moss, Fraser J, Page, Karen M, Pratt, Wendy S, Hunt, Steven P, Barclay, Jane, Rees, Michele, Dolphin, Annette C
• Format: Journal Article
• Language: English
• Published: United States 08.03.2002
• Subjects: Alleles; Amino Acid Sequence; Amino Acids - chemistry; Animals; Biotin - analogs & derivatives; Biotin - pharmacology; Cacna2d2 gene; Calcium Channels - chemistry; Calcium Channels - genetics; Calcium Channels, L-Type; Cerebellum - metabolism; Codon, Terminator; COS Cells; Dendrites - metabolism; Disease Models, Animal; DNA, Complementary - metabolism; Electrophysiology; Fluorescent Dyes - pharmacology; Genotype; Immunohistochemistry; In Situ Hybridization; Isoquinolines - pharmacology; Kinetics; Mice; Models, Biological; Molecular Sequence Data; Mutation; Phenotype; Protein Structure, Tertiary; Purkinje Cells - metabolism; Rats; RNA, Messenger - metabolism; Time Factors; Transfection; Xenopus
• DOI: 10.1074/jbc.M109404200
• ISSN: 0021-9258

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.