Rocker Is a New Variant of the Voltage-Dependent Calcium Channel Gene Cacna1a

• Published in: The Journal of neuroscience 2001-02, Vol.21 (4), p.1169-1178
• Main Authors: Zwingman, Theresa A, Neumann, Paul E, Noebels, Jeffrey L, Herrup, Karl
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Ataxia - etiology; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium Channels, N-Type; Calcium Channels, P-Type; Calcium Channels, Q-Type; Cerebellar Diseases - genetics; Cerebellar Diseases - pathology; Cerebellar Diseases - physiopathology; Cerebellum - pathology; Cerebellum - physiopathology; Chromosome Mapping; Crosses, Genetic; DNA Mutational Analysis; Female; Genes, Recessive; Genetic Complementation Test; Genetic Linkage - physiology; Genetic Markers; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Neurologic Mutants; Nerve Tissue Proteins - genetics; Point Mutation; Purkinje Cells - pathology; Tremor - etiology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.21-04-01169.2001

Rocker (gene symbol rkr), a new neurological mutant phenotype, was found in descendents of a chemically mutagenized male mouse. Mutant mice display an ataxic, unstable gait accompanied by an intention tremor, typical of cerebellar dysfunction. These mice are fertile and appear to have a normal life span. Segregation analysis reveals rocker to be an autosomal recessive trait. The overall cytoarchitecture of the young adult brain appears normal, including its gross cerebellar morphology. Golgi-Cox staining, however, reveals dendritic abnormalities in the mature cerebellar cortex characterized by a reduction of branching in the Purkinje cell dendritic arbor and a "weeping willow" appearance of the secondary branches. Using simple sequence length polymorphism markers, the rocker locus was mapped to mouse chromosome 8 within 2 centimorgans of the calcium channel alpha1a subunit (Cacna1a, formerly known as tottering) locus. Complementation tests with the leaner mutant allele (Cacna1a(la)) produced mutant animals, thus identifying rocker as a new allele of Cacna1a (Cacna1a(rkr)). Sequence analysis of the cDNA revealed rocker to be a point mutation resulting in an amino acid exchange: T1310K between transmembrane regions 5 and 6 in the third homologous domain. Important distinctions between rocker and the previously characterized alleles of this locus include the absence of aberrant tyrosine hydroxylase expression in Purkinje cells and the separation of the absence seizures (spike/wave type discharges) from the paroxysmal dyskinesia phenotype. Overall these findings point to an important dissociation between the seizure phenotypes and the abnormalities in catecholamine metabolism, and they emphasize the value of allelic series in the study of gene function.